Novel heterocyclic compound or salt thereof and intermediate thereof

ABSTRACT

Disclosed is a compound represented by the general formula: [wherein R 1  represents an aryl or heterocyclic group which may be substituted or the like; X 1  represents a C 2 -C 4  alkylene group or the like; X 2 , X 3  and X 5  independently represent NH, a bond or the like; X 4  represents a lower alkylene group, a bond or the like; Y 1  represents a bivalent alicyclic hydrocarbon residue which may be substituted or a bivalent alicyclic amine residue which may be substituted; and Z 1 , Z 2 , Z 3 , Z 4 , Z 5  and Z 6  independently represent a nitrogen atom, a group represented by the formula: CH, or the like, provided that at least one of Z 3 , Z 4 , Z 5  and Z 6  represents a nitrogen atom] or a salt thereof, which is useful as an antibacterial agent.

TECHNICAL FIELD

The present invention relates to novel compounds or salts thereof thathave strong antimicrobial activity against gram-positive bacteria,gram-negative bacteria and resistant bacteria, and relates toantimicrobial agents containing such compounds or salts. The presentinvention further relates to intermediates useful for producing suchcompounds.

BACKGROUND ART

In clinical practice, various types of antibiotics and syntheticantimicrobial agents have been used for treating infectious diseases.However, recently, resistant bacteria such as methicillin-resistantStaphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE),and penicillin-resistant Streptococcus pneumoniae (PRSP) have beenreported, and therapeutic treatment of patients infected with suchresistant bacteria is a critical issue. In addition, multidrug-resistantbacteria, which have developed resistance to a plurality of drugs, haveappeared. Infectious diseases due to multidrug-resistant bacteria areintractable and are severe problems worldwide.

The development of antibiotics effective on these resistant bacteria hasbeen strongly desired, and, for example, International PatentPublication No. WO 99/07682 (Patent Document 1) discloses quinolonecompounds that are effective against MRSA. International PatentPublication No. WO 2004/002490 (Patent Document 2) and WO 2004/002992(Patent Document 3) disclose compounds of which the working mechanismsare different from those of conventional medicaments.

Patent Document 1: International Patent Publication No. WO 99/07682

Patent Document 2: International Patent Publication No. Wo 2004/002490

Patent Document 3: International Patent Publication No. WO 2004/002992

DISCLOSURE OF THE INVENTION

The development of a medicament having strong antimicrobial activityagainst gram-positive bacteria, gram-negative bacteria, and resistantbacteria and having high safety has been desired. Furthermore, anintermediate useful for producing this medicament is highly desired.

Under such circumstances, the present inventors have conducted intensivestudies and, as a result, have found that a compound represented by ageneral formula [1]:

(wherein R¹ denotes an optionally substituted C₂-C₁₂ alkyl, aryl orheterocyclic group; X¹ denotes an optionally substituted C₂-C₄ alkylenegroup; X² denotes a group represented by a general formula NR² (where R²denotes a hydrogen atom, an optionally substituted lower alkyl group oran imino-protecting group) or a bond; X³ denotes a group represented bya general formula NR³ or CR⁴R⁵NR³ (where R³ denotes a hydrogen atom, anoptionally substituted lower alkyl group or an imino-protecting group;and R⁴ and R⁵ are the same or different and are each a hydrogen atom oran optionally substituted lower alkyl group, or R⁴ and R⁵ together forman oxo group) or a bond; X⁴ denotes an optionally substituted loweralkylene, lower alkenylene or lower alkynylene group or a bond; X⁵denotes an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonylgroup, a group represented by a general formula NR⁶ (where R⁶ denotes ahydrogen atom, an optionally substituted lower alkyl, lower alkenyl orlower alkynyl group or an imino-protecting group) or a bond; Y¹ denotesan optionally substituted bivalent alicyclic hydrocarbon residue or anoptionally substituted bivalent alicyclic amine residue; Z¹, Z², Z³, Z⁴,Z⁵ and Z⁶ are the same or different and are each a nitrogen atom or agroup represented by a general formula CR⁷ (where R⁷ denotes a hydrogenatom, a halogen atom, a hydroxyl group, a cyano group, a nitro group, aformyl group, an optionally protected or substituted amino group, anoptionally substituted lower alkyl, cycloalkyl, aryl, lower alkoxy,cycloalkyloxy, aralkyloxy, alkanoyl, ureido or monocyclic heterocyclicgroup, or a group represented by a general formula Q¹CONR¹R⁹, Q¹CO₂R¹⁰or Q¹CN (where R⁸ and R⁹ are the same or different and are each ahydrogen atom, an optionally substituted lower alkyl, cycloalkyl,aralkyl, aryl, lower alkoxy, alkanesulfonyl or monocyclic heterocyclicgroup, or form, together with the nitrogen atom to which R⁸ and R⁹ bind,an optionally substituted cyclic amino group; R^(1p) denotes a hydrogenatom or a carboxyl-protecting group; and Q¹ denotes an optionallysubstituted lower alkylene or lower alkenylene group or a bond)),provided that at least one of Z³, Z⁴, Z⁵ and Z⁶ is a nitrogen atom) or asalt thereof has strong antimicrobial activity and high safety; and thata compound represented by a general formula [2]:

(wherein X^(1a) denotes an optionally substituted C₁-C₃ alkylene group;Y² denotes an optionally protected carbonyl group; Z¹, Z², Z³, Z⁴, Z⁵and Z⁶ have the same meanings as mentioned above; and at least one ofZ³, Z⁴, Z⁵ and Z⁶ denotes a nitrogen atom) and a compound represented bya general formula [3]:

(wherein R^(7c) denotes a halogen atom, a hydroxyl group, a cyano group,a nitro group, a formyl group, an optionally protected or substitutedamino group, an optionally substituted lower alkyl, cycloalkyl, aryl,lower alkoxy, cycloalkyloxy, aralkyloxy, alkanoyl, ureido or monocyclicheterocyclic group, or a group represented by a general formulaQ¹CONR⁸R⁹, Q¹CO₂R¹⁰ or Q¹CN (where R⁸, R⁹, R¹⁰, and Q¹ have the samemeanings as mentioned above); Z^(2a) and Z^(6a) are the same ordifferent and are each a nitrogen atom or a group represented by ageneral formula CR⁷ (where R⁷ has the same meaning as mentioned above))are useful intermediates for the production of the compound of thegeneral formula [1]. The present invention has been accordinglycompleted.

The compound of the general formula [1] or a salt thereof has strongantimicrobial activity against gram-positive bacteria, gram-negativebacteria and resistant bacteria, and has high safety and is thereforeuseful as an excellent antimicrobial agent.

The compounds of the general formulas [2] and [3] are useful asintermediates for producing the compound of the general formula [1].

BEST MODE FOR CARRYING OUT THE INVENTION

The compound of the present invention will be described in detail.

In this description, unless otherwise specified, a halogen atom denotesa fluorine atom, a chlorine atom, a bromine atom or a iodine atom; analkyl group denotes, for example, a straight-chain or branched-chainC₁₋₁₂ alkyl group such as methyl, ethyl, propyl, isopropyl, butyl,sec-butyl, isobutyl, tert-butyl, pentyl, hexyl and octyl; a C₂-C₁₂ alkylgroup denotes, for example, a straight-chain or branched-chain C₂₋₁₂alkyl group such as ethyl, propyl, isopropyl, butyl, sec-butyl,isobutyl, tert-butyl, pentyl, hexyl and octyl; a lower alkyl groupdenotes, for example, a straight-chain or branched-chain C₁₋₆ alkylgroup such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl,isobutyl, tert-butyl, pentyl and isopentyl; an alkenyl group denotes,for example, a straight-chain or branched-chain C₂₋₁₂ alkenyl group suchas vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl,hexenyl, heptenyl and octenyl; a lower alkenyl group denotes, forexample, a straight-chain or branched-chain C₂₋₆ alkenyl group such asvinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl andhexenyl; a lower alkynyl group denotes, for example, a straight-chain orbranched-chain C₂₋₆ alkynyl group such as ethynyl, 2-propynyl and2-butynyl;

A cycloalkyl group denotes, for example, a C₃₋₈ cycloalkyl group such ascyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; an aryl groupdenotes, for example, such a group as phenyl, naphthyl, anthracenyl andphenanthrenyl; an aralkyl group denotes, for example, an ar-C₁₋₆ alkylgroup such as benzyl, diphenylmethyl, trityl, phenethyl andnaphthylmethyl;

A lower alkoxy group denotes, for example, a straight-chain orbranched-chain C₁₋₆ alkyloxy group such as methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy andisopentyloxy; a cycloalkyloxy group denotes, for example, a C₃₋₈cycloalkyloxy group such as cyclopropyloxy, cyclobutyloxy,cyclopentyloxy and cyclohexyloxy; an aralkyloxy group denotes, forexample, an ar-C₁₋₆ alkyloxy group such as benzyloxy and phenethyloxy;an alkoxyalkyl group denotes, for example, a C₁₋₆ alkyloxy C₁₋₆ alkylgroup such as methoxymethyl and 1-ethoxyethyl; an aralkyloxyalkyl groupdenotes, for example, an ar-C₁₋₆ alkyloxy C₁₋₆ alkyl group such asbenzyloxymethyl and phenethyloxymethyl;

A lower alkylene group denotes, for example, a C₁₋₆ alkylene group suchas methylene, ethylene, propylene, butylene and hexylene; a C₂-C₄alkylene group denotes, for example, a C₂₋₄ alkylene group such asethylene, propylene and butylene; a C₁-C₃ alkylene group denotes, forexample, a C₁₋₃ alkylene group such as methylene, ethylene andpropylene; a lower alkenylene group denotes, for example, a C₂₋₆alkenylene group such as vinylene, propenylene, butenylene andpentenylene; a lower alkynylene group denotes, for example, a C₂₋₆alkynylene group such as ethynylene, propynylene, butynylene andpentynylene;

An alkanoyl group denotes, for example, a straight-chain orbranched-chain C₂₋₁₂ alkanoyl group such as acetyl, propionyl, butyryl,isovaleryl and pivaloyl; an acyl group denotes, for example, a formylgroup, a straight-chain or branched-chain C₂₋₁₂ alkanoyl group such asacetyl, propionyl, butyryl, isovaleryl and pivaloyl, an ar-C₁₋₆alkylcarbonyl group such as benzylcarbonyl, a cyclichydrocarbon-carbonyl group such as benzoyl and naphthoyl, a heterocycliccarbonyl group such as nicotinoyl, thenoyl, pyrrolidinocarbonyl andfuroyl, a succinyl group, a glutaryl group, a maleoyl group, a phthaloylgroup, and a straight-chain or branched-chain α-aminoalkanoyl grouphaving an optionally protected N-terminal, which is derived from anamino acid (the amino acid is, for example, glycine, alanine, valine,leucine, isoleucine, serine, threonine, cysteine, methionine, asparticacid, glutamic acid, asparagine, glutamine, arginine, lysine, histidine,hydroxylysine, phenylalanine, tyrosine, tryptophan, proline andhydroxyproline);

An acylalkyl group denotes, for example, such a group as acetylmethyl,benzoylmethyl, p-nitrobenzoylmethyl, p-bromobenzoylmethyl,p-methoxybenzoylmethyl and 1-benzoylethyl; an acyloxy group denotes, forexample, a straight-chain or branched-chain C₂₋₆ alkanoyloxy group suchas acetyloxy and propionyloxy, and an aroyloxy group such as benzoyloxy;an acyloxyalkyl group denotes, for example, such a group asacetoxymethyl, propionyloxymethyl and pivaloyloxymethyl;

An alkyloxycarbonyl group denotes, for example, a straight-chain orbranched-chain C₁₋₁₂ alkyloxycarbonyl group such as methoxycarbonyl,ethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl,2-ethylhexyloxycarbonyl, tert-butoxycarbonyl and tert-pentyloxycarbonyl;an aralkyloxycarbonyl group denotes, for example, an ar-C₁₋₆alkyloxycarbonyl group such as benzyloxycarbonyl andphenethyloxycarbonyl; an aryloxycarbonyl group denotes, for example, aphenyloxycarbonyl group;

An alkylthio group denotes, for example, a C₁₋₆ alkylthio group such asmethylthio, ethylthio and propylthio; an arylthio group denotes, forexample, a phenylthio group; an alkylthioalkyl group denotes, forexample, a C₁₋₆ alkylthio C₁₋₆ alkyl group such as methylthiomethyl,ethylthiomethyl and propylthiomethyl; an arylthioalkyl group denotes,for example, such a group as (phenylthio)methyl and2-(p-nitrophenylthio)ethyl; an alkanesulfonyl group denotes, forexample, a C₁₋₆ alkanesulfonyl group such as methanesulfonyl,trifluoromethanesulfonyl, ethanesulfonyl and propanesulfonyl; anarylsulfonyl group denotes, for example, such a group asbenzenesulfonyl, toluenesulfonyl and naphthalenesulfonyl;

An arylsulfonylalkyl group denotes, for example, ap-toluenesulfonylethyl group; an alkanesulfonyloxy group denotes a C₁₋₆alkanesulfonyloxy group such as methanesulfonyloxy,trifluoromethanesulfonyloxy and ethanesulfonyloxy; an arylsulfonyloxygroup denotes, for example, such a group as benzenesulfonyloxy andtoluenesulfonyloxy;

A lower alkylamino group denotes, for example, a mono-C₁₋₆ alkylaminogroup such as methylamino, ethylamino, propylamino, isopropylamino,butylamino, tert-butylamino and pentylamino, a C₃₋₆ cycloalkylaminogroup such as cyclopropylamino, cyclobutylamino and cyclopentylamino,and a di-C₁₋₆ alkylamino group such as dimethylamino, diethylamino,dipropylamino and dibutylamino; a cyclic amino group denotes, forexample, such a group as piperazinyl, piperidinyl, morpholino andpyrrolidinyl; an oxygen-containing heterocyclic group denotes, forexample, such a group as 2-tetrahydropyranyl and 2-tetrahydrofuranyl; asulfur-containing heterocyclic group denotes, for example, atetrahydrothiopyranyl group;

An oxygen-containing heterocyclic alkyl group denotes, for example, a5-methyl-2-oxo-2H-1,3-dioxol-4-ylmethyl group; a nitrogen-containingheterocyclic alkyl group denotes, for example, such a group asphthalimidomethyl and succinimidomethyl; a heterocyclicoxycarbonyl groupdenotes, for example, such a group as 2-furfuryloxycarbonyl and8-quinolyloxycarbonyl;

A cycloalkylidene group denotes, for example, such a group ascyclopentylidene and cyclohexylidene; an aralkylidene group denotes, forexample, such a group as benzylidene and naphthylmethylene; adialkylaminoalkylidene group denotes, for example, such a group asN,N-dimethylaminomethylene and N,N-diethylaminomethylene; anitrogen-containing heterocyclic alkylidene group denotes, for example,a 3-hydroxy-4-pyridylmethylene group;

A diarylphosphoryl group denotes, for example, a diphenylphosphorylgroup; a di(aralkyl)phosphoryl group denotes, for example, adibenzylphosphoryl group; a substituted silyl group denotes, forexample, such a group as trimethylsilyl, triethylsilyl andtributylsilyl; an alkylsilylalkyl group denotes, for example, a2-(trimethylsilyl)ethyl group;

A monocyclic heterocyclic group denotes, for example, such a group asfuryl, furfuryl, thienyl, 2-thenyl, 2-pyrrolyl, imidazolyl, 3-pyrazolyl,thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, furazonyl,pyrrolidinyl, imidazolidinyl, pyridyl, pyrimidinyl, pyridazinyl,pyrazinyl, piperazinyl, 2-piperidyl, 3-piperidyl, 4-piperidyl,2-piperazinyl, 2-morpholinyl, 2-thiomorpholinyl and pyranyl; a bicyclicheterocyclic group denotes, for example, such a group as benzofuranyl,isobenzofuranyl, benzothienyl, indolyl, isoindolyl, indolizinyl,benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl,1H-indazolyl, purinyl, coumarinyl, chromenyl, quinolyl, isoquinolyl,phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl,chromanyl, isochromanyl, quinuclidinyl, 1,3-benzodioxanyl,1,4-benzodioxanyl, benzomorpholinyl, benzomorpholonyl,2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-yl,3,4-dihydro-2H-pyrido(4,3-b)(1,4)oxazin-7-yl,3-oxo-3,4-dihydro-2H-pyrido(3,2-b)(1,4)oxazin-6-yl,3-oxo-3,4-dihydro-2H-pyrido(3,2-b)(1,4)thiazin-6-yl,3-oxo-3,4-dihydro-2H-benzothiazin-6-yl,3,4-dihydro-2H-pyrano(2,3-c)pyridin-6-yl,3,4-dihydro-2H-(1,4)dioxepino(2,3-c)pyridin-8-yl,(1,3)dioxolo(4,5-c)pyridin-6-yl,6-oxide-2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-yl,7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl and5,6,7,8-tetrahydroquinoxalin-2-yl; a tricyclic heterocyclic groupdenotes, for example, such a group as thianthren-2-yl, xanthen-2-yl,phenoxathiin-2-yl, 4aH-carbazol-2-yl, carbazol-2-yl, phenanthridin-3-yl,acridin-2-yl, perimidin-2-yl, phenanthrolin-3-yl, phenazin-1-yl,phenothiazin-2-yl, phenoxazin-2-yl and2,3-dihydro-5-oxo-(1H,5H)-benzo(IJ)quinolin-6-yl; a heterocyclic groupdenotes, for example, the above-mentioned monocyclic heterocyclic,bicyclic heterocyclic or tricyclic heterocyclic group;

A protected carbonyl group denotes, for example, a group composed of acarbonyl group and an alcohol, such as (hydroxy)(methoxy)methylene,(hydroxy)(ethoxy)methylene, (hydroxy)(propoxy)methylene,(hydroxy)(isopropoxy)methylene, (hydroxy)(butoxy)methylene,(hydroxy)(pentyloxy)methylene, (hydroxy)(hexyloxy)methylene,(hydroxy)(heptyloxy)methylene, (hydroxy)(octyloxy)methylene,(hydroxy)(1,1-dimethylpropoxy)methylene, dimethoxymethylene,diethoxymethylene, dipropoxymethylene, diisopropoxymethylene,dibutoxymethylene, bis(benzyloxy)methylene, 1,3-dioxolan-2-ylidene and1,3-dioxan-2-ylidene, a group composed of a carbonyl group and a thiol,such as bis(methylthio)methylene, bis(ethylthio)methylene,bis(benzylthio)methylene, 1,3-dithiolan-2-ylidene and1,3-dithian-2-ylidene, and such a group as oxazolin-2-ylidene,imidazolidin-2-ylidene and thiazolidin-2-ylidene;

A bivalent alicyclic hydrocarbon residue denotes, for example, a C₃₋₈cycloalkylene residue such as 1,2-cyclobutylene, 1,3-cyclobutylene,1,2-cyclopentylene, 1,3-cyclopentylene, 1,2-cyclohexylene,1,3-cyclohexylene, and 1,4-cyclohexylene, and a cross-linked C₃₋₈cycloalkylene residue such as bicyclo(3.2.1)octylene,bicyclo(2.2.0)hexylene and bicyclo(5.2.0)nonylene; a bivalent 4-, 5- or6-membered alicyclic hydrocarbon residue denotes, for example, a C₄₋₆cycloalkylene residue such as 1,2-cyclobutylene, 1,3-cyclobutylene,1,2-cyclopentylene, 1,3-cyclopentylene, 1,2-cyclohexylene,1,3-cyclohexylene, and 1,4-cyclohexylene, and a cross-linked C₄₋₆cycloalkylene residue such as bicyclo(3.2.1)octylene andbicyclo(2.2.0)hexylene;

A bivalent alicyclic amine residue denotes, for example, a 4-memberedalicyclic amine residue such as azetidine-1,2-diyl andazetidine-1,3-diyl, a monocyclic 5-membered alicyclic amine residue suchas pyrrolidine-1,2-diyl and pyrrolidine-1,3-diyl, a cross-linked5-membered alicyclic amine residue such as3-azabicyclo(3.1.0)hexane-3,5-diyl, 3-azabicyclo(3.1.0)hexane-3,6-diyl,8-azabicyclo(3.2.1)octane-3,8-diyl,octahydrocyclopenta(c)pyrrole-2,4-diyl,octahydrocyclopenta(c)pyrrole-2,5-diyl,octahydropyrrolo[3,4-c]pyrrole-2,4-diyl andoctahydropyrrolo[3,4-c]pyrrole-2,5-diyl, a monocyclic 6-memberedalicyclic amine residue such as piperidine-1,3-diyl,piperidine-1,4-diyl, piperazine-1,3-diyl, piperazine-1,4-diyl,morpholine-2,4-diyl and thiomorpholine-2,4-diyl, a cross-linked6-membered alicyclic amine residue such as3-azabicyclo(4.1.0)heptane-3,6-diyl andhexahydroimidazo[1,5-a]pyrazine-2,7-diyl, and a homopiperazine-1,4-diylgroup;

A bivalent 5-membered alicyclic amine residue denotes, for example, amonocyclic 5-membered alicyclic amine residue such aspyrrolidine-1,2-diyl and pyrrolidine-1,3-diyl, and a cross-linked5-membered alicyclic amine residue such as3-azabicyclo(3.1.0)hexane-3,5-diyl, 3-azabicyclo(3.1.0)hexane-3,6-diyl,8-azabicyclo(3.2.1)octane-3,8-diyl,octahydrocyclopenta(c)pyrrole-2,4-diyl,octahydrocyclopenta(c)pyrrole-2,5-diyl,octahydropyrrolo[3,4-c]pyrrole-2,4-diyl andoctahydropyrrolo[3,4-c]pyrrole-2,5-diyl; and a bivalent 6-memberedalicyclic amine residue denotes, for example, a monocyclic 6-memberedalicyclic amine residue such as piperidine-1,3-diyl,piperidine-1,4-diyl, piperazine-1,3-diyl, piperazine-1,4-diyl,morpholine-2,4-diyl and thiomorpholine-2,4-diyl, and a cross-linked6-membered alicyclic amine residue such as3-azabicyclo(4.1.0)heptane-3,6-diyl andhexahydroimidazo[1,5-a]pyrazine-2,7-diyl.

Examples of an imino-protecting group include all groups that can begenerally used as an imino-protecting group, for example, thosedisclosed in W. Greene, et al., Protective Groups in Organic Synthesis,3rd Ed., pp. 494-653, 1999, John Wiley & Sons, INC. More specificexamples include an acyl group, an alkyloxycarbonyl group, anaralkyloxycarbonyl group, an aryloxycarbonyl group, an aralkyl group, analkoxyalkyl group, an aralkyloxyalkyl group, an arylthio group, analkanesulfonyl group, an arylsulfonyl group, a diarylphosphoryl group, adi(aralkyl)phosphoryl group, an oxygen-containing heterocyclic alkylgroup and a substituted silyl group.

Examples of an amino-protecting group include all groups that can begenerally used as an amino-protecting group, for example, thosedisclosed in W. Greene, et al., Protective Groups in Organic Synthesis,3rd Ed., pp. 494-653, 1999, John Wiley & Sons, INC. More specificexamples include an acyl group, an alkyloxycarbonyl group, anaralkyloxycarbonyl group, an aryloxycarbonyl group, an aralkyl group, analkoxyalkyl group, an aralkyloxyalkyl group, an arylthio group, analkanesulfonyl group, an arylsulfonyl group, a dialkylaminoalkylidenegroup, an aralkylidene group, a nitrogen-containing heterocyclicalkylidene group, a cycloalkylidene group, a diarylphosphoryl group, adi(aralkyl)phosphoryl group, an oxygen-containing heterocyclic alkylgroup and a substituted silyl group.

Examples of a hydroxyl-protecting group include all groups that can begenerally used as a hydroxyl-protecting group, for example, thosedisclosed in W. Greene, et al., Protective Groups in Organic Synthesis,3rd Ed., pp. 17-245, 1999, John Wiley & Sons, INC. More specificexamples include an acyl group, an alkyloxycarbonyl group, anaralkyloxycarbonyl group, a heterocyclicoxycarbonyl group, an alkylgroup, an alkenyl group, an aralkyl group, an oxygen-containingheterocyclic group, a sulfur-containing heterocyclic group, analkoxyalkyl group, an aralkyloxyalkyl group, an alkanesulfonyl group, anarylsulfonyl group and a substituted silyl group.

Examples of a carboxyl-protecting group include all groups that can begenerally used as a carboxyl-protecting group, for example, thosedisclosed in W. Greene, et al., Protective Groups in Organic Synthesis,3rd Ed., pp. 369-453, 1999, John Wiley & Sons, INC. More specificexamples include an alkyl group, an aryl group, an aralkyl group, anacylalkyl group, an arylthioalkyl group, an arylsulfonylalkyl group, anoxygen-containing heterocyclic group, an alkylsilylalkyl group, anacyloxyalkyl group, a nitrogen-containing heterocyclic alkyl group, acycloalkyl group, an alkoxyalkyl group, an aralkyloxyalkyl group, analkylthioalkyl group, an alkenyl group and a substituted silyl group.

A leaving group is, for example, a halogen atom, an alkanesulfonyloxygroup, an arylsulfonyloxy group and an acyloxy group.

In general, the salt of the compound of the general formula [1] includescommonly known salts formed from a basic group such as an amino group,or from an acid group such as a phenolic hydroxyl group or a carboxylgroup.

Examples of the salts formed from a basic group include salts withmineral acids such as hydrochloric acid, hydrobromic acid and sulfuricacid; salts with organic carboxylic acids such as tartaric acid, formicacid, acetic acid, citric acid, trichloroacetic acid and trifluoroaceticacid; and salts with sulfonic acids such as methanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acidand naphthalenesulfonic acid.

Examples of the salts formed from an acid group include salts withalkali metals such as sodium and potassium; salts with alkaline-earthmetals such as calcium and magnesium; ammonium salts; and salts withnitrogen-containing organic bases such as trimethylamine, triethylamine,tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine,N-methylmorpholine, diethylamine, dicyclohexylamine, procaine,dibenzylamine, N-benzyl-β-phenethylamine andN,N′-dibenzylethylenediamine.

Furthermore, among the above-mentioned salts, pharmacologicallyacceptable salts are preferable as salts of the compound of the generalformula [1].

For example,1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-onetrihydrochloride is nonhygroscopic and is a particularly preferablesalt.

Examples of substituents for the C₂-C₁₂ alkyl group, aryl group andheterocyclic group of R¹ include one or more groups selected from ahalogen atom, optionally protected hydroxyl and carboxyl groups, loweralkyl, lower alkenyl, lower alkynyl and lower alkoxy groups which may besubstituted by one or more halogen atoms, a hydroxyimino group, an acylgroup, a protected amino group, an amino group, a lower alkylaminogroup, an alkylthio group, an aryl group, a monocyclic heterocyclicgroup, an oxo group, and the like. Examples of the preferredsubstituents include one or more groups selected from a halogen atom,optionally protected hydroxyl and carboxyl groups, lower alkyl, loweralkenyl and lower alkoxy groups which may be substituted by one or morehalogen atoms, a lower alkylamino group, an aryl group, a monocyclicheterocyclic group, and an oxo group. Examples of the more preferredsubstituents include one or more groups selected from a halogen atom, ahydroxyl group, a carboxyl group, a methyl group, an ethyl group, atert-butyl group, a trifluoromethyl group, a vinyl group, a methoxygroup, an ethoxy group, a trifluoromethoxy group, a dimethylamino group,a phenyl group, a thienyl group, a pyrrolidinyl group and an oxo group.Examples of the further preferred substituents include one or moregroups selected from a halogen atom, a methyl group, an ethyl group, athienyl group and an oxo group.

Examples of substituents for the lower alkyl groups of R², R³, R⁴ and R⁵and for the lower alkyl group, lower alkenyl group and lower alkynylgroup of R⁶ include one or more groups selected from a halogen atom,optionally protected hydroxyl and carboxyl groups, lower alkyl, loweralkenyl, lower alkynyl and lower alkoxy groups which may be substitutedby one or more halogen atoms, lower alkyl, lower alkenyl and loweralkynyl groups which may be substituted by one or more aryl groups, anaryl group, a monocyclic heterocyclic group, and the like. Examples ofthe preferred substituents include one or more groups selected from ahalogen atom, optionally protected hydroxyl and carboxyl groups, a loweralkyl group which may be substituted by one or more halogen atoms, and alower alkynyl group which may be substituted by one or more aryl groups.Examples of the more preferred substituents include one or more groupsselected from a halogen atom, a hydroxyl group, a carboxyl group, amethyl group, an ethyl group, a trifluoromethyl group, a 2-phenylethynylgroup and an oxo group. Examples of further preferred substituentsinclude a carboxyl group and a 2-phenylethynyl group.

Examples of substituents for the lower alkyl group, cycloalkyl group,aryl group, lower alkoxy group, cycloalkyloxy group, aralkyloxy group,alkanoyl group, ureido group and monocyclic heterocyclic group of R⁷,for the lower alkyl group and lower alkoxy group of R^(7a), for thelower alkyl group and lower alkoxy group of R^(7b), for the lower alkylgroup, cycloalkyl group, aryl group, lower alkoxy group, cycloalkyloxygroup, aralkyloxy group, alkanoyl group, ureido group and monocyclicheterocyclic group of R^(7c), for the lower alkyl group and lower alkoxygroup of R^(7d), and for the lower alkyl group, cycloalkyl group,aralkyl group, aryl group, lower alkoxy group, alkanesulfonyl group andmonocyclic heterocyclic group of R⁸ and R⁹ include one or more groupsselected from a halogen atom, optionally protected hydroxyl and carboxylgroups, lower alkyl, lower alkenyl, lower alkynyl and lower alkoxygroups which may be substituted by one or more halogen atoms, ahydroxyimino group, an aryl group, a monocyclic heterocyclic group, andthe like. Examples of the preferred substituents include one or moregroups selected from a halogen atom, optionally protected hydroxyl andcarboxyl groups, lower alkyl and lower alkoxy groups which may besubstituted by one or more halogen atoms, and a monocyclic heterocyclicgroup. Examples of the more preferred substituents include one or moregroups selected from a halogen atom, a hydroxyl group, a carboxyl group,a methyl group and a methoxy group.

Examples of substituents for the amino group of R⁷ include one or moregroups selected from lower alkyl, lower alkenyl, lower alkynyl and loweralkoxy groups which may be substituted by one or more halogen atoms, anacyl group, an aryl group, a monocyclic heterocyclic group, and thelike. Examples of the preferred substituents include one or more groupsselected from lower alkyl and lower alkenyl groups which may besubstituted by one or more halogen atoms, an acyl group, and an arylgroup. Examples of the more preferred substituents include one or moregroups selected from a methyl group, an ethyl group, a trifluoromethylgroup, a vinyl group, a formyl group, an acetyl group, a benzoyl groupand a phenyl group. Examples of the further preferred substituentsinclude one or more groups selected from a methyl group, an ethyl group,an acetyl group and a phenyl group.

Examples of substituents for the cyclic amino group formed by R⁸ and R⁹together with the nitrogen atom to which they bind include one or moregroups selected from a halogen atom, optionally protected hydroxyl andcarboxyl groups, lower alkyl, lower alkenyl, lower alkynyl and loweralkoxy groups which may be substituted by one or more halogen atoms, ahydroxyimino group, an acyl group, an amino group, a lower alkylaminogroup, an alkylthio group, an aryl group, a monocyclic heterocyclicgroup which may be substituted by one or more aralkyl groups, an oxogroup, and the like. Examples of the preferred substituents include oneor more groups selected from a halogen atom, optionally protectedhydroxyl and carboxyl groups, lower alkyl, lower alkenyl and loweralkoxy groups which may be substituted by one or more halogen atoms, analkanoyl group, a lower alkylamino group, an alkylthio group, an arylgroup, a monocyclic heterocyclic group which may be substituted by oneor more aralkyl groups, and an oxo group. Examples of the more preferredsubstituents include one or more groups selected from a halogen atom, ahydroxyl group, a carboxyl group, a methyl group, an ethyl group, amethoxy group, an ethoxy group, a dimethylamino group, a phenyl groupand an oxo group.

Examples of substituents for the lower alkylene group and loweralkenylene group of Q¹ include one or more groups selected from an oxogroup, optionally protected hydroxyl and carboxyl groups, a lower alkylgroup, a lower alkenyl group, a lower alkynyl group, a lower alkoxygroup, an aryl group, and the like. Examples of the preferredsubstituents include one or more groups selected from an oxo group,optionally protected hydroxyl and carboxyl groups, a lower alkyl group,a lower alkoxy group, and an aryl group. Examples of the more preferredsubstituents include one or more groups selected from an oxo group, ahydroxyl group, a carboxyl group, a methyl group, a methoxy group and aphenyl group.

Examples of substituents for the C₂-C₄ alkylene group of X¹, for theC₁-C₃ alkylene group of X^(1a), and for the lower alkylene group, loweralkenylene group and lower alkynylene group of X⁴ include one or moregroups selected from an oxo group, optionally protected hydroxyl andcarboxyl groups, a lower alkyl group, a lower alkenyl group, a loweralkynyl group, a lower alkoxy group, an aryl group, and the like.Examples of the preferred substituents include one or more groupsselected from an oxo group and a lower alkyl group. Examples of the morepreferred substituents include one or more groups selected from an oxogroup and a methyl group.

Examples of substituents for the bivalent alicyclic hydrocarbon residueand bivalent alicyclic amine residue of Y¹ include one or more groupsselected from a halogen atom, optionally protected hydroxyl and carboxylgroups, lower alkyl, lower alkenyl, lower alkynyl and lower alkoxygroups which may be substituted by one or more halogen atoms, ahydroxyimino group, an acyl group, an amino group, a lower alkylaminogroup, an alkylthio group, an aryl group, a monocyclic heterocyclicgroup which may be substituted by one or more aralkyl groups, an oxogroup, and the like. Examples of the preferred substituents include oneor more groups selected from a halogen atom, optionally protectedhydroxyl and carboxyl groups, lower alkyl, lower alkenyl and loweralkoxy groups which may be substituted by one or more halogen atoms, analkanoyl group, a lower alkylamino group, an alkylthio group, an arylgroup, a monocyclic heterocyclic group which may be substituted by oneor more aralkyl groups, and an oxo group. Examples of the more preferredsubstituents include one or more groups selected from a halogen atom, ahydroxyl group, a carboxyl group, a methyl group, an ethyl group, amethoxy group, an ethoxy group, a dimethylamino group, a phenyl groupand an oxo group.

In the compounds of the general formula [1] of the present invention,examples of the preferred compounds are as follows:

Preferred are the compounds wherein R¹ is an optionally substituted arylor heterocyclic group. More preferred are the compounds wherein R¹ is3-fluoro-4-methylphenyl, 3-fluoro-4-(trifluoromethyl)phenyl,3-fluoro-4-methylpyridyl, 5-fluoro-6-methylpyridyl, 4-ethylphenyl,naphthyl, benzo(b)thiophen-2-yl, benzo[b)thiophen-5-yl,benzo[b)thiophen-6-yl, 5-(thiophen-2-yl)isoxazol-2-yl,2,3-dihydro-1,4-benzodithiin-6-yl, 2,3-dihydrobenzo(1,4)dioxin-6-yl,2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-yl,3-oxo-3,4-dihydro-2H-pyrido(3,2-b)(1,4)oxazin-6-yl,7-chloro-3-oxo-3,4-dihydro-2H-pyrido(3,2-b)(1,4)thiazin-6-yl,3-oxo-3,4-dihydro-2H-pyrido(3,2-b)(1,4)thiazin-6-yl or3-oxo-3,4-dihydro-2H-benzothiazin-6-yl. Further preferred are thecompounds wherein R¹ is 2,3-dihydrobenzo(1,4)dioxin-6-yl,2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-yl or3,4-dihydro-2H-pyrano(2,3-c)pyridin-6-yl, and further more preferred arethe compounds wherein R¹ is 2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-yl.

Preferred are the compounds wherein X¹ is an optionally substitutedethylene group, and more preferred are the compounds wherein X¹ is anethylene group.

Preferred are the compounds wherein X² is NH or a bond, and morepreferred are the compounds wherein X² is a bond.

Preferred are the compounds wherein X³ is NH, CH₂NH or a bond, and morepreferred are the compounds wherein X³ is NH or a bond, and furtherpreferred are the compounds wherein X³ is NH.

Preferred are the compounds wherein X⁴ is an optionally substitutedlower alkylene group or a bond, and more preferred are the compoundswherein X⁴ is a lower alkylene group, and further preferred are thecompounds wherein X⁴ is a methylene group.

Preferred are the compounds wherein X⁵ is an oxygen atom, a sulfur atom,NH or a bond, and more preferred are the compounds wherein X⁵ is a bond.

Preferred are the compounds wherein Y¹ is an optionally substitutedbivalent 4-, 5- or 6-membered alicyclic hydrocarbon residue or anoptionally substituted bivalent 5- or 6-membered alicyclic amineresidue. More preferred are the compounds wherein Y¹ is an optionallysubstituted bivalent 6-membered alicyclic hydrocarbon residue or anoptionally substituted bivalent 6-membered alicyclic amine residue, andfurther preferred are the compounds wherein Y¹ is an optionallysubstituted cyclohexylene, piperazinediyl or piperidinediyl group, andfurther more preferred are the compounds wherein Y¹ is apiperidine-1,4-diyl group (the nitrogen atom in the 1-position binds toX²).

Preferred are the compounds wherein Z¹ has the general formula CR⁷(where R⁷ has the same meaning as mentioned above), and more preferredare the compounds wherein Z¹ has the general formula CR^(7a) (whereR^(7a) denotes a hydrogen atom, a halogen atom, a hydroxyl group, anoptionally substituted lower alkyl or lower alkoxy group), and furtherpreferred are the compounds wherein Z¹ is CH.

Preferred are the compounds wherein Z² has the general formula CR⁷(where R⁷ has the same meaning as mentioned above), and more preferredare the compounds wherein Z² is a group represented by the generalformula CR^(7a) (where R^(7a) has the same meaning as mentioned above),and further preferred are the compounds wherein Z² is CH.

Preferred are the compounds wherein Z³ is a nitrogen atom or a grouprepresented by the general formula CR^(7a) (where R^(7a) has the samemeaning as mentioned above), and more preferred are the compoundswherein Z³ is a nitrogen atom or CH, and further preferred are thecompounds wherein Z³ is a nitrogen atom.

Preferred are the compounds wherein Z⁴ is a nitrogen atom or a grouprepresented by the general formula CR^(7a) (where R^(7a) has the samemeaning as mentioned above), and more preferred are the compoundswherein Z⁴ is a nitrogen atom or CH, and further preferred are thecompounds wherein Z⁴ is CH.

Preferred are the compounds wherein Z⁵ has the general formula CR⁷(where R⁷ has the same meaning as mentioned above), and more preferredare the compounds wherein Z⁵ has the general formula CR^(7b) (whereR^(7b) denotes a hydrogen atom, a halogen atom, an optionallysubstituted lower alkyl or lower alkoxy group), and further preferredare the compounds wherein Z⁵ has the general formula CR^(7d) (whereR^(7d) denotes a halogen atom, an optionally substituted lower alkyl orlower alkoxy group), and further more preferred are the compoundswherein Z⁵ has the general formula CR^(7e) (where R⁷, denotes a halogenatom, a lower alkyl group or a lower alkoxy group).

Preferred are the compounds wherein Z⁶ is a nitrogen atom or a grouprepresented by the general formula CR^(7a) (where R^(7a) has the samemeaning as mentioned above), and more preferred are the compoundswherein Z⁶ is a nitrogen atom or CH.

Examples of the most preferable compounds of the general formula [1] ofthe present invention are:

-   7-Chloro-1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-1,5-naphthyridin-2(1H)-one,    1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one,    1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-one,    and    5-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-3-methoxypyrido(2,3-b)pyrazin-6(5H)-one.

Examples of typical compounds of the general formula [1] of the presentinvention are those shown in Tables 1A to 3B.

TABLE 1A

Z³ Z⁴ Z⁵ Z⁶ R³ R^(a) X⁴—X⁵—R¹ CH CH C(OCH₃) N H H2,3-dihydro-1,4-benzodioxin-6-ylmethyl CH CH C(OCH₃) N H H2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl CH CH CH N H H2,3-dihydro-1,4-benzodioxin-6-ylmethyl CH CH CH N H H7-chloro-2H-pyrido(3,2-b)(1,4)thiazin-3(4H)-on-6- ylmethyl CH CH CH N HH 2H-1,4-benzoxazin-3(4H)-on-6-ylmethyl CH CH N CH H H1-benzothiophen-2ylmethyl CH CH N CH H H 2-naphthylmethyl CH CH N CH H H3-fluoro-4-methylbenzyl CH CH N CH H H 4-ethylbenzyl CH CH N CH H H5-(2-thienyl)isoxazol-3-ylmethyl CH CH N CH H N7-chloro-2H-pyrido(3,2-b)(1,4)thiazin-3(4H)on-6- ylmethyl CH CH N CH H H2H-pyrido(3,2-b)(1,4)thiazin-3(4H)-on-6-ylmethyl CH CH N CH H H2,3-dihydro-1,4-benzodioxin-6-ylmethyl CH CH N CH H H2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl CH CH N CH H HCH₂C≡CC₆H₅ CH CH N CH H H 2H-1,4-benzoxazin-3(4H)-on-E-ylmethyl CH CH NCH CH₂C≡CC₆H₅ H CH₂C≡CC₆H₅ CH N CH CH H H2,3-dihydro-1,4-benzodioxin-6-ylmethyl N CH C(OCH₃) CH H H3-fluoro-4-methylbenzyl N CH C(OCH₃) CH H H3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]-oxazin-6- ylmethyl N CH C(OCH₃)CH H H 2,3-dihydro(1,4)dioxino(2,3-b)pyridan-7-ylmethyl N CH C(OCH₃) CHH N 2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl N CH C(OCH₃) CH H H5,6,7,8-tetrahydroquinoxalin-2-ylmethyl N CH C(OCH₃) CH CH₂CO₂H H2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl N CH C(OCH₃) CH N CH₃2,3dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl N CH C(OCH₃) N H H2,3-dihydro(1,4)dioxino(2,3-c)pyridirl-7-ylmethyl N CH CCH₃ CH H H2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl N CH CH CH H H2,3-dihydro-1,4-benzodioxin-6-ylmethyl N CH CH CH H H2,3dihydro(1,4)dioxino(2,3-c)pyridin7ylmethyl N CH CH CH H H2H-pyrido(3,2-b)(1,4)thiazin-3(4H)-on-6-ylmethyl N CH CCH═CHCO₂C₂H₅ CH HH 2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl N CH CCl CH H H2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl N CH CCN CH H N2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl N CH CF CH H H2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl

TABLE 1B

Z³ Z⁴ Z⁵ Z⁶ R³ R^(a) X⁴—X⁵—R¹ N CH C(OCH₃) CH H H(5-fluoro-2-methylpyridin-3-yl)methyl N CH C(OCH₃) CH H H4-fluoro-3-methylbenzyl N CH C(OCH₃) CH H H2H-pyrido(3,2-b)(1,4)thiazin-3(4H)-on-6-yl N CH C-Im CH H H2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl N CH C(OCH₃) CH H H(5-fluoro-6-methylpyridin-3-yl)methyl N CH C(OCH₃) H H H(5-fluoro-6-methylpyridin-3-yl)methyl CH H C(OCH₃) H H H2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl N CH CF CH H H(5-fluoro-6-methoxypyridin-3-yl)methyl N CH CF CH H H(5-fluoro-2,6-dimethylpyridin3yl)methyl N CH CF CH H H(3,4-dihydro-2H-pyrano(2,3-c)pyridin-6-yl)methyl N CH CF CH H H(5-fluoro-6-methylpyridin-3-yl)methyl N CH CF CH H H(3,4-dihydro-2H-(1,4)dioxepino(2,3-c)pyridin-8-yl)methyl N CH CF CH H H((1,3)dioxolo(4,5-c)pyridin-6-yl)methyl N CH C(NH₃) CH H H2,3-dihydro(1,4)dioxino(2,3-c)pyridin-6-ylmethyl N CH CF CH H H(3,4-dihydro-2H-pyrido(4,3b)(1,4)oxazin-7-yl)methyl N CH CF CH H H3-(pyrazin-2yl)prop-2-in-1-yl N CH C(OCH₃) CH H H(3,4-dihydro-2H-(1,4)dioxepino(2,3-c)pyridin-8-yl)methyl N CH C(OCH₃) CHH H (6-oxido-2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-yl)methyl N CHC(OCH₃) CH H H (5-ethylpyridin-2-yl)methyl N CH CF CH H H3-fluoro-4-methylbenzoyl N CH CF CH H H(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-yl)carbonyl N CH C(OCH₃) CH H H(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)methyl N CH C(OCH₃) CH HH (4-methoxy-5-methylpyridin-2-yl)methyl N CH C(OCH₃) CH H H(5-ethyl-4-methoxypyridin-2-yl)methyl N CH C(OCH₃) CH H H(5-methoxy-4-methylpyridin-2-yl)methyl N CH C(OCH₃) CH H H(5-(3-thienyl)isoxazol-3-yl)methyl N CH C(OCH₃) CH H H6-(3-thienyl)pyridin-2-yl)methyl N CH C(OCH₃) CH H H(5-fluoro-6-methoxypyridin-3-yl)methyl N CH C(OCH₃) CH H H(6-ethyl-5-fluoropyridin-3-yl)methyl N CH C(OCH₃) CH H H(5-fluoro-6-(pyrrolidin-1-yl)pyridin-3-yl)methyl N CH C(OCH₃) CH H H(5-(2-furyl)isoxazol-3-yl)methyl N CH C(OCH₃) CH H H(5-(2-thienyl)pyridin-3-yl)methyl N CH C(OCH₃) CH H H(6-(2-thienyl)pyridin-3-yl)methyl N CH CF CH H H(5-(2-furyl)isoxazol-3-yl)methyl N CH C(OCH₃) CH H H(3,4-dihydro-2H-pyrano(2,3-c)pyridin-6-yl)methyl N CH C(OCH₃) CH H H(5-(2-furyl)pyridin-3-yl)methyl N CH C(OCHF₂) CH H H2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl N CH C(OCH₃) CH H H(T,5-naphthyridin-3-yl)methyl N CH C(OCH₃) CH H H(6-(2-furyl)pyrazin-2-yl)methyl N CH C-Oxa CH H H2,3-clihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl N CH C-Thia CH H H2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl N CH CF CH H H(5,6,7,8-tetrahydroquinoxalin-2-yl)methyl N CH CF CH H H(5-(2-furyl)-1,3-oxazol-2-yl)methyl N CH CF CH H H(3,4-dihydro-2H-pyrano(3,2-c)pyridin-7-yl(methyl N CH C(OCH₃) CH H H(3,4-dihydro-2H-pyrano(3,2-c)pyridin-7-yl)methyl N CH C(CF₃) CH H H2,3dihydro(T,4)dioxino(2,3-c)pyridin-7-ylmethyl N CMe CF CH H H2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl N CMe C(OCH₃) CH H H2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl N CH CF CH H H(2,3-dihydro(1,4)dioxino(2,3-b)pyridin-7-yl)methyl N CH CBr CH H H2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl N CH CNH₂ CH H H2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl N CH C(OCH₃) CH H H(5-methyl-4-oxo-4H-pyran-2-yl)methyl N CH C(OCH₃) CH H H(5-aminopyrazin-2-yl)methyl Im: 1H-imidazol-1-yl, Oxa: 1,3-oxazol-2-yl,Thia: 1,3-thiazol-2-yl

TABLE 2

Z³ Z⁴ Z⁵ Z⁶ X⁴—X⁵—R¹ CH N CH CH 2,3-dihydro-1,4-benzodioxin-6-ylmethylCH CH CH N 2,3-dihydro-1,4-benzodioxin-6-ylmethyl N CH CH CH2,3-dihydro-1,4-benzodioxin-6-ylmethyl CH CH C(OCH₃) N2,3-dihydro-1,4-dioxino(2,3-c)pyridin-7-ylmethyl CH CH N CH2,3-dihydro-1,4-benzodioxin-6-ylmethyl CH CH C(OCH₃) N2H-pyrido(3,2-b)(1,4)-thiazin-3(4H)-on-6-ylmethyl N CH C(OCH₃) CH3,4-dihydro-2H-(1,4)-dioxepino(2,3-c)pyridin-8-ylmethyl CH CH CF N2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl N CH C(OCH₃) CH2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl CH CH CNH2 N2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl CH CH C-Tri N2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl

TABLE 3A

TABLE 3B

In the compounds of the general formula [2] of the present invention,examples of the preferred compounds are as follows:

Preferred are the compounds wherein X^(1a) is a methylene group or anethylene group, and more preferred are the compounds wherein X^(1a) is amethylene group.

Preferred are the compounds wherein Y² is a 1,3-dioxolan-2-ylidenegroup, a (hydroxy)(methoxy)methylene group, a dimethoxymethylene groupor a carbonyl group, and more preferred are compounds wherein Y² is a1,3-dioxolan-2-ylidene group, a dimethoxymethylene group or a carbonylgroup, and further preferred are the compounds wherein Y² is adimethoxymethylene group or a carbonyl group, and further more preferredare the compounds wherein Y² is a carbonyl group.

Preferred are the compounds wherein Z¹ has the general formula CR⁷(where R⁷ has the same meaning as mentioned above), and more preferredare the compounds wherein Z¹ is a group represented by the generalformula CR^(7a) (where R^(7a) has the same meaning as mentioned above),and further preferred are the compounds wherein Z¹ is CH.

Preferred are the compounds wherein Z² has the general formula CR⁷(where R⁷ has the same meaning as mentioned above), and more preferredare the compounds wherein Z² is a group represented by the generalformula CR^(7a) (where R^(7a) has the same meaning as mentioned above),and further preferred are the compounds wherein Z² is CH.

Preferred are the compounds wherein Z³ is a nitrogen atom or a grouprepresented by the general formula CR^(7a) (where R^(7a) has the samemeaning as mentioned above), and more preferred are the compoundswherein Z³ is a nitrogen atom or CH, and further preferred are thecompounds wherein Z³ is a nitrogen atom.

Preferred are the compounds wherein Z⁴ is a nitrogen atom or a grouprepresented by the general formula CR^(7a) (where R^(7a) has the samemeaning as mentioned above), and more preferred are the compoundswherein Z⁴ is a nitrogen atom or CH, and further preferred are thecompounds wherein Z⁴ is CH.

Preferred are the compounds wherein Z⁵ has the general formula CR⁷(where R⁷ has the same meaning as mentioned above), and more preferredare the compounds wherein Z⁵ has the general formula CR^(7a) (whereR^(7a) has the same meaning as mentioned above), and further preferredare the compounds wherein Z⁵ has the general formula CR^(7d) (whereR^(7d) has the same meaning as mentioned above), and further morepreferred are the compounds wherein Z⁵ has the general formula CR^(7e)(where R^(7e) has the same meaning as mentioned above).

Preferred are the compounds wherein Z⁶ is a nitrogen atom or a grouprepresented by the general formula CR^(7a) (where R^(7a) has the samemeaning as mentioned above), and more preferred are the compoundswherein Z⁶ is a nitrogen atom or CH.

Examples of the typical compounds of the general formula [2] of thepresent invention are those shown in Tables 4A to 4B.

TABLE 4A

Z³ Z⁵ Z⁶ Y² N CH CH CO N CF CH CO N CCH₃ CH CO N C(OCH₃) CH CO CH CH NCO CH CF N CO CH CCH₃ N CO CH C(OCH₃) N CO N CH N CO N CF N CO N CCH₃ NCO N C(OCH₃) N CO N CH CH 1,3-dioxolan--2-ylidene N CF CH1,3-dioxolan-2-ylidene N CCH₃ CH 1,3-dioxolan-2-ylidene N C(OCH₃) CH1,3-dioxc1˜n-2-ylidene CH CH N 1,3-dioxolan-2-ylidene CH CF N1,3-dioxolan-2-ylidene CH CCH₃ N 1,3-dioxolan-2-ylidene CH C(OCH₃) N1,3-dioxolan-2-ylidene N CH N 1,3-dioxolan-2-ylidene N CF N1,3-dioxolan-2-ylidene N CCH₃ N 1,3-dioxolan-2-ylidene N C(OCH₃) N1,3-dioxolan-2-ylidene

TABLE 4B

Z³ Z⁵ Z⁶ Y² N CH CH dimethoxymethylene N CF CH dimethoxymethylene N CCH₃CH dimethoxymethylene N C(OCH₃) CH dimethoxymethylene CH CH Ndimethoxymethylene CH CF N dimethoxymethylene CH CCH₃ Ndimethoxymethylene CH C(OCH₃) N dimethoxymethylene N CH Ndimethoxymethylene N CF N dimethoxymethylene N CCH₃ N dimethoxymethyleneN C(OCH₃) N dimethoxymethylene N CH CH (hydroxy)(methoxy)methylene N CFCH (hydroxy)(methoxy)methylene N CCH₃ CH (hydroxy)(methoxy)methylene NC(OCH₃) CH (hydroxy)(methoxy)methylene CH CH N(hydroxy)(methoxy)methylene CH CF N (hydroxy)(methoxy)methylene CH CCH₃N (hydroxy)(methoxy)methylene CH C(OCH₃) N (hydroxy)(methoxy)methylene NCH N (hydroxy)(methoxy)methylene N CF N (hydroxy)(methoxy)methylene NCCH₃ N (hydroxy)(methoxy)methylene N C(OCH₃) N(hydroxy)(methoxy)methylene

In the compounds of the general formula [3] of the present invention,examples of the preferred compounds are as follows:

Preferred are the compounds wherein R^(7c) is a halogen atom or anoptionally substituted lower alkyl or lower alkoxy group.

Preferred are the compounds wherein Z^(2a) has the general formula CR⁷(where R⁷ has the same meaning as mentioned above), and more preferredare the compounds wherein Z^(2a) is CH.

Preferred are the compounds wherein Z^(6a) is a nitrogen atom or CH.

Examples of the typical compounds of the general formula [3] of thepresent invention are those shown in Table 5.

TABLE 5

Z^(6a) R^(7c) CH F CH CH₃ CH OCH₃ N F N CH₃ N OCH₃

Methods of producing the compounds of the present invention will now bedescribed.

The compounds of the general formula [1] of the present invention can beproduced by a combination of known methods. For example, the compoundscan be produced by the following production methods.

(In the formulas, Y^(1a) denotes an optionally substituted bivalentalicyclic amine residue wherein one nitrogen atom in the ring binds toan adjacent group and another atom in the ring binds to X³; and R¹,X^(1a), X³, X⁴, X⁵, Z¹, Z², Z³, Z⁴, Z⁵ and Z⁶ have the same meanings asmentioned above.)

Examples of known compounds of the general formula [4a] include4-((1-phenylethyl)amino)-piperidine, tert-butyl(3-aminobenzyl)(4-piperidinyl)carbamate andphenyl-N-(4-piperidinyl)carboxamide.

A compound of the general formula [1a] can be produced by reacting acompound of the general formula [2a] with the compound of the generalformula [4a] in the presence of a reducing agent.

This reaction may be carried out by the method described in, forexample, International Patent Publication Nos. WO 02/50061 and WO02/56882, Jerry Mar., Advanced Organic Chemistry, 4th Ed., pp. 898-900,1992, John Wiley & Sons, INC., or Richard C. Larock, ComprehensiveOrganic Transformations, pp. 421-425, 1989, VCH Publishers, INC. or amethod according to the method.

In this reaction, any solvent that does not adversely affect thereaction can be used, and examples thereof include alcohols such asmethanol, ethanol, 2-propanol, and 2-methyl-2-propanol; halogenatedhydrocarbons such as methylene chloride, chloroform, and dichloroethane;aromatic hydrocarbons such as benzene, toluene, and xylene; ethers suchas dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether,diethylene glycol dimethyl ether, diethylene glycol diethyl ether, andethylene glycol monomethyl ether; sulfoxides such as dimethyl sulfoxide;esters such as ethyl acetate; amides such as N,N-dimethylformamide,N,N-dimethylacetamide, and 1-methyl-2-pyrrolidone; and water. Thesesolvents may be used as a mixture thereof.

Examples of the reducing agent used in this reaction include hydridecomplex compounds such as lithium aluminum hydride, sodiumtriacetoxyborohydride, sodium cyanoborohydride, and sodium borohydride;borane, sodium, and sodium amalgam. In addition, electrolysis reductionusing a copper or platinum anode, catalytic reduction using Raneynickel, platinum oxide, or palladium black, or reduction using“zinc-acid” can be employed.

In this reaction, the amounts of the compound of the general formula[4a] and the reducing agent may be 1 to 50-fold moles, preferably 1 to5-fold moles to that of the compound of the general formula [2a].

This reaction may be carried out at −30 to 150° C., preferably at 0 to100° C., for 10 minutes to 120 hours.

(In the formulas, X^(2a) is a group represented by a general formulaNR^(2a) (where R^(2a) denotes a hydrogen atom or an optionallysubstituted lower alkyl group); and R¹, X^(1a), X³, X⁴, X⁵, Y¹, Z¹, Z²,Z³, Z⁴, Z⁵ and Z⁶ have the same meanings as mentioned above.)

Examples of known compounds of the general formula [4b] include4-amino-1-(1-oxo-2-phenylethyl)piperidine and4-amino-1-(2-phenylethyl)piperidine.

A compound of the general formula [1b] can be produced by reacting thecompound of the general formula [2a] with a compound of the generalformula [4b] in the presence of a reducing agent. This reaction may becarried out according to the production method 1.

(In the formulas, Y^(1b) denotes an optionally substituted bivalentalicyclic amine residue wherein one nitrogen atom in the ring binds toan adjacent group and another atom in the ring binds to X²; and R¹, X¹,X², X⁴, X⁵, Z¹, Z², Z³, Z⁴, Z⁵ and Z⁶ have the same meanings asmentioned above.)

Examples of known compounds of the general formula [6] include1,4-benzodioxane-6-carbaldehyde and(2,3-dihydro-1,4-benzodioxin-6-yl)acetaldehyde.

A compound of the general formula [1c] can be produced by reacting acompound of the general formula [5] with the compound of the generalformula [6] in the presence of a reducing agent. This reaction may becarried out according to the production method 1.

(In the formulas, X^(3a) is a group represented by a general formulaNR^(3a) or CR⁴R⁵NR^(3a) (where R^(3a) denotes a hydrogen atom or anoptionally substituted lower alkyl group; and R⁴ and R⁵ have the samemeanings as mentioned above); and R¹, X¹, X², X⁴, X⁵, Y¹, Z¹, Z², Z³,Z⁴, Z⁵ and Z⁶ have the same meanings as mentioned above.)

A compound of the general formula [1d] can be produced by reacting acompound of the general formula [7] with the compound of the generalformula [6] in the presence of a reducing agent. This reaction may becarried out according to the production method 1.

(In the formulas, L¹ denotes a leaving group; and R¹, X¹, X², X⁴, X⁵,Y¹, Z¹, Z³, Z⁴, Z⁵ and Z⁶ have the same meanings as mentioned above.)

Examples of known compounds of the general formula [8] include2-(3-oxo-3,4-dihydro-2H-benzothiazin-6-yl)ethyl methanesulfonate,2-(benzo[1,3]dioxol-5-yl)ethyl methanesulfonate,2-((2-bromoethyl)thio)thiophene and 2-bromo-N-(pyridin-2-yl)acetamide.

A compound of the general formula [1e] can be produced by reacting thecompound of the general formula [5] with a compound of the generalformula [8] in the presence or absence of a base. This reaction may becarried out by the method described in, for example, U.S. Pat. No.6,603,005 or a method according to the method.

In this reaction, any solvent that does not adversely affect thereaction can be used, and examples thereof include alcohols such asmethanol, ethanol, 2-propanol, and 2-methyl-2-propanol; halogenatedhydrocarbons such as methylene chloride, chloroform, and dichloroethane;aromatic hydrocarbons such as benzene, toluene, and xylene; ethers suchas dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether,diethylene glycol dimethyl ether, diethylene glycol diethyl ether, andethylene glycol monomethyl ether; sulfoxides such as dimethyl sulfoxide;ketones such as acetone and 2-butanone; esters such as ethyl acetate;amides such as N,N-dimethylformamide, N,N-dimethylacetamide, and1-methyl-2-pyrrolidone; and water. These solvents may be used as amixture thereof.

In this reaction, examples of the base used according to need includeorganic bases such as pyridine, dimethylaminopyridine, andtriethylamine; and inorganic bases such as sodium hydroxide, potassiumhydroxide, sodium hydrogen carbonate, potassium carbonate, and sodiumcarbonate.

In this reaction, the amounts of the compound of the general formula [8]and the base used according to need may be 1 to 20-fold moles to that ofthe compound of the general formula [5].

This reaction may be carried out at 0 to 200° C., preferably at 0 to150° C., for 30 minutes to 48 hours.

(In the formulas, R¹, L¹, X¹, X², X^(3a), X⁴, X⁵, Y¹, Z¹, Z², Z³, Z⁴, Z⁵and Z⁶ have the same meanings as mentioned above.)

A compound of the general formula [1f] can be produced by reacting thecompound of the general formula [7] with a compound of the generalformula [8] in the presence or absence of a base. This reaction may becarried out according to the production method 5.

(In the formulas, L² denotes a leaving group; and R¹, X¹, X², X³, X⁴,X⁵, Y¹, Z¹, Z², Z³, Z⁴, Z⁵ and Z⁶ have the same meanings as mentionedabove.)

Examples of known compounds of the general formula [9] include2-(4-(phenylacetyl)piperazin-1-yl)ethyl chloride and2-chloro-1-(4-phenethylpiperazin-1-yl)ethanone.

The compound of the general formula [1] can be produced by reacting acompound of the general formula [3a] with the compound of the generalformula [9] in the presence or absence of a base.

In this reaction, any solvent that does not adversely affect thereaction can be used, and examples thereof include amides such asN,N-dimethylformamide, N,N-dimethylacetamide, and1-methyl-2-pyrrolidone; halogenated hydrocarbons such as methylenechloride, chloroform, and dichloroethane; aromatic hydrocarbons such asbenzene, toluene, and xylene; ethers such as dioxane, tetrahydrofuran,anisole, ethylene glycol dimethyl ether, diethylene glycol dimethylether, diethylene glycol diethyl ether, and ethylene glycol monomethylether; sulfoxides such as dimethyl sulfoxide; esters such as ethylacetate; and water. These solvents may be used as a mixture thereof.

In this reaction, examples of the base used according to need includeorganic bases such as pyridine, dimethylaminopyridine, andtriethylamine; and inorganic bases such as sodium hydride, sodiumhydroxide, potassium hydroxide, sodium hydrogen carbonate, potassiumcarbonate, sodium carbonate, and cesium carbonate.

In this reaction, the amounts of the base used according to need and thecompound of the general formula [9] may be 1 to 50-fold moles,preferably 1 to 5-fold moles to that of the compound of the generalformula [3a].

This reaction may be carried out at −30 to 150° C., preferably at 0 to100° C., for 30 minutes to 48 hours.

The compounds of the general formulas [1], [1a], [1b], [1c], [1d], [1e]and [1f] prepared in the production methods 1 to 7 or salts thereof canbe derived to other compounds of the general formula [1] or saltsthereof by a known reaction such as condensation, addition, oxidation,reduction, rearrangement, substitution, halogenation, dehydration, orhydrolysis, or by a proper combination of such reactions.

In the compounds in the above-mentioned production methods, when isomers(for example, enantiomers, geometric isomers, or tautomers) exist, theseisomers also can be used. Furthermore, solvates, hydrates, and variousforms of crystals can be used.

The compounds of the general formula [2] of the present invention can beproduced by a combination of known methods. For example, the compoundscan be produced by the following production methods.

(In the formulas, Y^(2a) denotes a protected carbonyl group; L³ denotesa leaving group; and X^(1a), Z¹, Z², Z³, Z⁴, Z⁵ and Z⁶ have the samemeanings as mentioned above.)

Examples of known compounds of the general formula [10] include2-(2-bromomethyl)-1,3-dioxolane, 2-(2-bromoethyl)-1,3-dioxolane and2-(2-bromoethyl)-1,3-dioxane.

(8-1) A compound of the general formula [2b] can be produced by reactingthe compound of the general formula [3a] with a compound of the generalformula [10] in the presence or absence of a base. This reaction may becarried out according to the production method 7.

(8-2) The compound of the general formula [2a] can be produced bydeprotecting the compound of the general formula [2b]. This reaction maybe carried out by the method described in, for example, ProtectiveGroups in Organic Synthesis, 3rd Ed., pp. 293-368, 1999, John Wiley &Sons, INC. or a method according to the method.

(In the formulas, R¹⁶ denotes a chlorine atom, a bromine atom, a iodineatom, or an optionally substituted alkanesulfonyloxy group; R¹⁷ denotesa carboxyl-protecting group; and X^(1a), Y^(2a), Z³, Z⁴, Z⁵ and Z⁶ havethe same meanings as mentioned above.)

An example of a compound of the general formula [11] is2-chloro-N-(2,2-dimethoxyethyl)pyridine-3-amine.

Examples of a compound of the general formula [12] include methylacrylate, ethyl acrylate and tert-butyl acrylate.

(9-1) A compound of the general formula [13] can be produced by reactingthe compound of the general formula [11] with the compound of thegeneral formula [12] in the presence of a catalyst, in the presence orabsence of a base, and in the presence or absence of a ligand. Thisreaction may be carried out by the method described in, for example,Tsuji, et al., Sen-i Kinzoku ga Hiraku Yuki Gosei (Organic synthesisusing transition metal), pp. 19-22, 1997, Maruzen and Chem. Pharm.Bull., vol. 33, pp. 4764-4768, 1985 or a method according to the method.

In this reaction, any solvent that does not adversely affect thereaction can be used, and examples thereof include alcohols such asmethanol, ethanol, 2-propanol, and 2-methyl-2-propanol; amides such asN,N-dimethylformamide, N,N-dimethylacetamide, and1-methyl-2-pyrrolidone; halogenated hydrocarbons such as methylenechloride, chloroform, and dichloroethane; aromatic hydrocarbons such asbenzene, toluene, and xylene; ethers such as dioxane, tetrahydrofuran,anisole, ethylene glycol dimethyl ether, diethylene glycol dimethylether, diethylene glycol diethyl ether, and ethylene glycol monomethylether; sulfoxides such as dimethyl sulfoxide; ketones such as acetoneand 2-butanone; esters such as ethyl acetate; nitrites such asacetonitrile; and water. These solvents may be used as a mixturethereof. This reaction may be carried out in the absence of a solvent.

Examples of the catalyst used in this reaction includetetrakis(triphenylphosphine)palladium(0), palladium(II) acetate,palladium(II) chloride, bis(tri-tert-butylphosphine)palladium(0), andtris(dibenzylideneacetone)dipalladium(0).

In this reaction, examples of the base used according to need includeorganic bases such as pyridine, dimethylaminopyridine, triethylamine,N,N-dimethylbenzylamine, sodium acetate, and potassium acetate; andinorganic bases such as sodium hydroxide, potassium hydroxide, sodiumhydrogen carbonate, potassium carbonate, and sodium carbonate.

In this reaction, examples of the ligand used according to need includetrialkylphosphines such as trimethylphosphine andtri-tert-butylphosphine; tricycloalkylphosphines such astricyclohexylphosphine; triarylphosphines such as triphenylphosphine andtritolylphosphine; trialkylphosphites such as trimethylphosphite,triethylphosphite, and tributylphosphite; tricycloalkylphosphites suchas tricyclohexylphosphite; triarylphosphites such as triphenylphosphite;imidazolium salts such as 1,3-bis(2,4,6-trimethylphenyl)imidazoliumchloride; diketones such as acetylacetone and octafluoroacetylacetone;amines such as trimethylamine, triethylamine, tripropylamine, andtriisopropylamine; and 1,1-bis(diphenylphosphino)ferrocene,2,2′-bis(diphenylphosphino)-1,1′-binaphthyl,2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl,2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl,2-(di-tert-butylphosphino)-2′,4′,61-triisopropylbiphenyl, and2-(di-tert-butylphosphino)biphenyl. These ligands may be used as acombination thereof.

In this reaction, the amount of the compound of the general formula [12]is 1 to 10-fold moles, preferably 1 to 5-fold moles to that of thecompound of the general formula [11].

In this reaction, the amount of the catalyst is 0.001 to 10-fold moles,preferably 0.01 to 2-fold moles to that of the compound of the generalformula [11].

In this reaction, the amount of the base used according to need is 1 to10-fold moles, preferably 1 to 5-fold moles to that of the compound ofthe general formula [11].

In this reaction, the amount of the ligand used according to need is0.00001 to 1-fold moles, preferably 0.001 to 0.1-fold moles to that ofthe compound of the general formula [11].

This reaction may be carried out at −30 to 200° C., preferably at 0 to100° C., for 30 minutes to 48 hours.

(9-2) A compound of the general formula [2c] can be produced byring-closing the compound of the general formula [13] in the presence orabsence of a base. This reaction may be carried out by the methoddescribed in, for example, Chem. Pharm. Bull., vol. 33, pp. 4764-4768,1985 or a method according to the method.

In this reaction, any solvent that does not adversely affect thereaction can be used, and examples thereof include alcohols such asmethanol, ethanol, 2-propanol, and 2-methyl-2-propanol; amides such asN,N-dimethylformamide, N,N-dimethylacetamide, and1-methyl-2-pyrrolidone; aromatic hydrocarbons such as benzene, toluene,and xylene; ethers such as dioxane, tetrahydrofuran, anisole, ethyleneglycol dimethyl ether, diethylene glycol dimethyl ether, diethyleneglycol diethyl ether, and ethylene glycol monomethyl ether; sulfoxidessuch as dimethyl sulfoxide; ketones such as acetone and 2-butanone;esters such as ethyl acetate; nitrites such as acetonitrile; and water.These solvents may be used as a mixture thereof.

In this reaction, examples of the base used according to need includeorganic bases such as pyridine, dimethylaminopyridine, andtriethylamine; and inorganic bases such as sodium methoxide, sodiumethoxide, sodium hydroxide, potassium hydroxide, sodium hydrogencarbonate, potassium carbonate, and sodium carbonate.

In this reaction, the amount of the base used according to need may be 1to 20-fold moles to that of the compound of the general formula [13].

This reaction may be carried out at 0 to 200° C., preferably at 0 to150° C., for 30 minutes to 48 hours.

(9-3) A compound of the general formula [2d] can be produced bydeprotecting the compound of the general formula [2c]. This reaction maybe carried out according to the production method 8-2.

(In the formulas, R^(7f) denotes a hydrogen atom or an optionallysubstituted lower alkyl, cycloalkyl or aryl group; R¹⁸ denotes ahydrogen atom or a carboxyl-protecting group; X^(1a), Y^(2a), Z³, Z⁴, Z⁵and Z⁶ have the same meanings as mentioned above.)

An example of a compound of the general formula [15] is ethylglyoxylate. In this reaction, the compound of the general formula [15]may be a hydrate (hemiacetal) thereof. An example of the hydrate(hemiacetal) of the compound of the general formula [15] is ethylglyoxylate hemiacetal.

(10-1) A compound of the general formula [2e] can be produced byreacting a compound of the general formula [14] with the compound of thegeneral formula [15]. This reaction may be carried out by the methoddescribed in, for example, J. Chem. Soc., pp. 5156-5166, 1963 or amethod according to the method.

(10-2) A compound of the general formula [2f] can be produced bydeprotecting the compound of the general formula [2e]. This reaction maybe carried out according to the production method 8-2.

The compounds of the general formula [3] of the present invention can beproduced by a combination of known methods. For example, the compoundscan be produced by the following production methods.

(In the formulas, R^(7c), R¹⁶, R¹⁷, and Z^(6a) have the same meanings asmentioned above.)

Examples of a compound of the general formula [16] include3-amino-2-chloro-5-methoxypyridine and3-amino-2-chloro-5-methoxypyrazine.

(11-1) A compound of the general formula [17] can be produced byreacting the compound of the general formula [16] with the compound ofthe general formula [12] in the presence of a catalyst and in thepresence or absence of a base. This reaction may be carried outaccording to the production method 9-1.

(11-2) The compound of the general formula [3b] can be produced byring-closing the compound of the general formula [17] in the presence orabsence of a base. This reaction may be carried out according to theproduction method 9-2.

(In the formulas, R^(7c), R¹⁸ and Z^(6a) have the same meanings asmentioned above.)

A compound of the general formula [3c] can be produced by reacting acompound of the general formula [18] with a compound of the generalformula [15a]. This reaction may be carried out according to theproduction method 10-1.

(In the formulas, Z^(2a), Z^(6a), and R^(7c) have the same meanings asmentioned above.)

(13-1) A compound of the general formula [33] can be produced byoxidizing a compound of the general formula [32].

This reaction may be carried out by the method described in, forexample, Heterocycles, vol. 32, pp. 1579-1586, 1991 or Heterocycles,vol. 34, pp. 1055-1063, 1992 or a method according to the method.

In this reaction, any solvent that does not adversely affect thereaction can be used, and examples thereof include halogenatedhydrocarbons such as methylene chloride, chloroform, and dichloroethane;aromatic hydrocarbons such as benzene, toluene, and xylene; sulfoxidessuch as dimethyl sulfoxide; and water. These solvents may be used as amixture thereof.

Examples of the oxidant used in this reaction are m-chloroperbenzoicacid and peracetic acid.

In this reaction, the amount of the oxidant may be 1 to 10-fold moles tothat of the compound of the general formula [32].

This reaction may be carried out at 0 to 200° C., preferably at 0 to 50°C., for 30 minutes to 48 hours.

(13-2) The compound of the general formula [3] can be produced byreacting the compound of the general formula [33] with a sulfonylchloride and then hydrating the resulting product.

This reaction may be carried out by the method described in, forexample, Heterocycles, vol. 32, pp. 1579-1586, 1991 or Heterocycles,vol. 34, pp. 1055-1063, 1992 or a method according to the method.

In this reaction, any solvent that does not adversely affect thereaction can be used together with water, and examples thereof includehalogenated hydrocarbons such as methylene chloride, chloroform, anddichloroethane; aromatic hydrocarbons such as benzene, toluene, andxylene; sulfoxides such as dimethyl sulfoxide; nitrites such asacetonitrile. These solvents may be used as a mixture thereof.

Examples of the sulfonyl chlorides used in this reaction includep-toluenesulfonyl chloride and benzenesulfonyl chloride.

In this reaction, the amount of the sulfonyl chloride may be 1 to10-fold moles to that of the compound of the general formula [33].

This reaction may be carried out at 0 to 200° C., preferably at 0 to 50°C., for 30 minutes to 48 hours.

The compounds of the general formula [1] of the present invention can bealso produced by the following production methods.

(In the formulas, Y^(1c) denotes an optionally substituted bivalentalicyclic hydrocarbon residue wherein one carbon atom in the ring or ofa substituent is substituted with an oxo group or denotes an optionallysubstituted bivalent alicyclic amine residue wherein one carbon atom inthe ring or of a substituent is substituted with an oxo group; and R¹,X¹, X², X^(3a), X⁴, X⁵, Y¹, Z¹, Z², Z³, Z⁴, Z⁵ and Z⁶ have the samemeanings as mentioned above.)

An example of known compounds of the general formula [6a] is1-(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-yl)methaneamine.

The compound of the general formula [1f] can be produced by reacting acompound of the general formula [5b] with the compound of the generalformula [6a] in the presence of a reducing agent. This reaction may becarried out according to the production method 1.

Next, methods of producing the compounds of the general formulas [5],[7] and [14], which are raw materials for producing the compounds of thegeneral formulas [1], [2] and [3] of the present invention, will bedescribed. These compounds can be produced by a combination of knownmethods. For example, the compounds can be produced by the followingproduction methods.

(In the formulas, R¹⁶, R¹⁷, Z³, Z⁴, Z⁵ and Z⁶ have the same meanings asmentioned above.)

Examples of a compound of the general formula [16a] include3-amino-2-chloro-5-methoxypyridine and3-amino-2-chloro-5-methoxypyrazine.

(A-1) A compound of the general formula [17a] can be produced byreacting the compound of the general formula [16a] with the compound ofthe general formula [12] in the presence of a catalyst and in thepresence or absence of a base. This reaction may be carried outaccording to the production method 9-1.

(A-2) A compound of the general formula [3d] can be produced byring-closing the compound of the general formula [17a] in the presenceor absence of a base. This reaction may be carried out according to theproduction method 9-2.

(In the formulas, R⁷, R¹⁸, Z³, Z⁴, Z⁵ and Z⁶ have the same meanings asmentioned above.)

A compound of the general formula [3e] can be produced by reacting acompound of the general formula [18a] with the compound of the generalformula [15]. This reaction may be carried out according to theproduction method 10-1.

(In the formulas, R¹⁹ denotes an imino-protecting group; L⁴ denotes aleaving group; and X¹, X², Y^(1b), Z¹, Z², Z³, Z⁴, Z⁵ and Z⁶ have thesame meanings as mentioned above.)

An example of known compounds of the general formula [19] is1-tert-butyl 4-ethyl4-(2-(methanesulfonyloxy)ethyl)-1,4-piperidinedicarboxylate.

(C-1) A compound of the general formula [20] can be produced by reactingthe compound of the general formula [3a] with the compound of thegeneral formula [19] in the presence or absence of a base. This reactionmay be carried out according to the production method 7.

(C-2) The compound of the general formula [5] can be produced bydeprotecting the compound of the general formula [20]. This reaction maybe carried out by the method described in, for example, ProtectiveGroups in Organic Synthesis, 3rd Ed., pp. 494-653, 1999, John Wiley &Sons, INC. or a method according to the method.

(In the formulas, R²⁰ denotes an imino-protecting group; L⁵ denotes aleaving group; X¹, X², X^(3a), Y¹, Z¹, Z², Z³, Z⁴, Z⁵ and Z⁶ have thesame meanings as mentioned above.)

An example of known compounds of the general formula [21] is tert-butyl((1-(2-chloroacetyl)-4-(3-(trifluoromethyl)phenyl)-4-piperidyl)methyl)(methyl)carbamate.

(D-1) A compound of the general formula [22] can be produced by reactingthe compound of the general formula [3a] with the compound of thegeneral formula [21] in the presence or absence of a base. This reactionmay be carried out according to the production method 7.

(D-2) The compound of the general formula [7] can be produced bydeprotecting the compound of the general formula [22]. This reaction maybe carried out according to the production method C-2.

(In the formulas, R²¹ denotes an imino-protecting group; Y^(1c) denotesan optionally substituted bivalent alicyclic amine residue wherein twonitrogen atoms in the ring bind to each other's adjacent groups; andX^(1a), Z¹, Z² Z³, Z⁴, Z⁵ and Z⁶ have the same meanings as mentionedabove.)

Examples of a compound of the general formula [23] include1-(tert-butoxycarbonyl)piperazine and methyl4-(tert-butoxycarbonyl)piperazine-2-carboxylate.

(E-1) A compound of the general formula [20a] can be produced byreacting the compound of the general formula [2a] with a compound of thegeneral formula [23] in the presence of a reducing agent. This reactionmay be carried out according to the production method 1.

(E-2) A compound of the general formula [5a] can be produced bydeprotecting the compound of the general formula [20a]. This reactionmay be carried out according to the production method C-2.

(In the formulas, R²² denotes an imino-protecting group; X^(1a), X^(3a),Y^(1a), Z¹, Z², Z³, Z⁴, Z⁵ and Z⁶ have the same meanings as mentionedabove.)

An example of a compound of the general formula [24] is4-((benzyloxycarbonyl)amino)-4-methylpiperidine.

(F-1) A compound of the general formula [22a] can be produced byreacting the compound of the general formula [2a] with the compound ofthe general formula [24] in the presence of a reducing agent. Thisreaction may be carried out according to the production method 1.

(F-2) A compound of the general formula [7a] can be produced bydeprotecting the compound of the general formula [22a]. This reactionmay be carried out according to the production method C-2.

(In the formulas, R²³ denotes an imino-protecting group; and R¹, X⁴, X⁵,and Y^(1c) have the same meanings as mentioned above.)

(G-1) A compound of the general formula [26] can be produced by reactinga compound of the general formula [25] with the compound of the generalformula [6] in the presence of a reducing agent. This reaction may becarried out according to the production method 1.

(G-2) A compound of the general formula [4c] can be produced bydeprotecting the compound of the general formula [26]. This reaction maybe carried out according to the production method C-2.

(In the formulas, R²⁴ denotes an imino-protecting group; and R¹, X^(3a),X⁴, X⁵, and Y^(1a) have the same meanings as mentioned above.)

(H-1) A compound of the general formula [28] can be produced by reactinga compound of the general formula [27] with the compound of the generalformula [6] in the presence of a reducing agent. This reaction may becarried out according to the production method 1.

(H-2) A compound of the general formula [4d] can be produced bydeprotecting the compound of the general formula [28]. This reaction maybe carried out according to the production method C-2.

(In the formulas, Y^(2a), Z³, Z⁴, Z⁵ and Z⁶ have the same meanings asmentioned above.)

Examples of a compound of the general formula [29] include3-nitropyridin-2-amine and 3-amino-2-nitropyridine.

Examples of a compound of the general formula [30] include2,2-dimethoxyacetaldehyde and 2,2-diethoxyacetaldehyde.

(I-1) A compound of the general formula [31] can be produced by reactingthe compound of the general formula [29] with the compound of thegeneral formula [30] in the presence of a reducing agent. This reactionmay be carried out according to the production method 1.

(I-2) A compound of the general formula [14a] can be produced byreducing the compound of the general formula [31]. This reaction may becarried out by the method described in, for example, Richard C. Larock,Comprehensive Organic Transformations, pp. 411-415, 1989, VCHPublishers, INC. or a method according to the method.

(In the formulas, X^(1b) denotes an optionally substituted methylene orethylene group or a bond; and R¹⁷, X^(1a), Y^(2a), Z³, Z⁴, Z⁵ and Z⁶have the same meanings as mentioned above.)

The compound of the general formula [13] can be produced by reacting thecompound of the general formula [17a] with a compound of the generalformula [30b] in the presence of a reducing agent. This reaction may becarried out according to the production method 1.

(In the formulas, Y^(1d) denotes an optionally substituted bivalentalicyclic hydrocarbon residue wherein one carbon atom in the ring or ofa substituent is that of a protected carbonyl group or denotes anoptionally substituted bivalent alicyclic amine residue wherein onecarbon atom in the ring or of a substituent is that of a protectedcarbonyl group; and R¹⁷, X¹, X^(1a), X², Y^(1c), Z¹, Z², Z³, Z⁴, Z⁵ andZ⁶ have the same meanings as mentioned above.)

(K-1) A compound of the general formula [13b] can be produced byreacting a compound of the general formula [17b] with a compound of thegeneral formula [30a] in the presence of a reducing agent. This reactionmay be carried out according to the production method 1.

(K-2) A compound of the general formula [5c] can be produced byring-closing the compound of the general formula [13b] in the presenceor absence of a base. This reaction may be carried out according to theproduction method 9-2.

(K-3) A compound of the general formula [5b] can be produced bydeprotecting the compound of the general formula [5c] in the presence orabsence of a base. This reaction may be carried out according to theproduction method 8-2.

The compounds prepared in the production methods 1 to 14 and theproduction methods A to K can be derived to other compounds by a knownreaction such as condensation, addition, oxidation, reduction,rearrangement, substitution, halogenation, dehydration, or hydrolysis,or by a proper combination of such reactions.

When an imino, amino, hydroxyl, or carboxyl group exists in thecompounds prepared in the production methods 1 to 14 and the productionmethods A to K and intermediates thereof, the reactions can be carriedout with such groups appropriately protected with their protectinggroups.

In the production methods 1 to 14 and the production methods A to K,when a compound having a carbonyl group is used in a reaction, acompound having a protected carbonyl group can be used instead of thecompound having a carbonyl group.

When the compound of the general formula [1] of the present invention isused as a drug, in general, formulation additives, for example, anexcipient, a carrier, and a diluent, which are used in preparation, maybe appropriately mixed with the compound. These mixtures can beadministered, in the usual manner, orally or parenterally in forms of,for example, tablets, capsules, powder, syrup, granules, pills,suspensions, emulsions, solutions, powdered medicine, suppositories,eye-drops, nose-drops, ear drops, plasters, ointment or injections. Theadministration route, dose, and frequency can be appropriatelydetermined depending on the age, body weight, and symptoms of a patient.In general, the compound may be administered to an adult orally orparenterally (for example, injection, infusion, or administration intothe rectum) in an amount of 0.01 to 1000 mg/kg per day at once or inseveral divided doses.

The compound of the general formula [1] of the present invention hasstrong antimicrobial activity against, for example, gram-positivebacteria including resistant bacteria such as multidrug-resistantStaphylococcus aureus, multidrug-resistant pneumococcus, andvancomycin-resistant Enterococcus, gram-negative bacteria, anaerobes, oratypical mycobacteria.

More specifically, the compound of the general formula [1] of thepresent invention has strong antimicrobial activity against, forexample, bacteria selected from Staphylococcus aureus (Staphylococcusaureus Smith, Staphylococcus aureus F-3095 (MDRSA), and Staphylococcusaureus F-2161 (MDRSA)), pneumococcus (Streptococcus pneumoniae IID553,Streptococcus pneumoniae D-1687 (QRSP) and Streptococcus pneumoniaeD-4249 (MDRSP)), Enterococcus faecalis (Enterococcus faecalis ATCC29212,Enterococcus faecalis IID682, Enterococcus faecalis D-2648 (VCM-R), andEnterococcus faecalis EF-210 (VanA)), Enterococcus faecium (Enterococcusfaecium NBRC 13712 and Enterococcus faecium EF-211 (VanA)),Corynebacterium diphtheriae (Corynebacterium diphtheriae ATCC 27010),Escherichia coli (Escherichia coli NIHJ), Serratia marcescens (Serratiamarcescens IID 5218), Haemophilus influenzae (Haemophilus influenzaeATCC 49247), Moraxella catarrhalis (Moraxella catarrhalis ATCC 25238),Pseudomonas aeruginosa (Pseudomonas aeruginosa IF03445), Enterobactercloacae (Enterobacter cloacae IID 977), Citrobacter freundii(Citrobacter freundii NBRC 12681), Gardnerella vaginalis (Gardnerellavaginalis ATCC 14018), Neisseria gonorrhoeae (Neisseria gonorrhoeae ATCC19424), Peptostreptococcus asaccharolyticus (Peptostreptococcusasaccharolyticus ATCC 14963), Propionibacterium acnes (Propionibacteriumacnes JCM 6425), Clostridium perfringens (Clostridium perfringens ATCC13124), Bacteroides fragilis (Bacteroides fragilis ATCC 25285),Porphyromonas gingivalis (Porphyromonas gingivalis JCM 8525), Prevotellaintermedia (Prevotella intermedia JCM 7365), Fusobacterium nucleatum(Fusobacterium nucleatum JCM 8532), Legionella pneumophilia (Legionellapneumophilia ATCC33153, Legionella pneumophilia subsp. pneumophiliaATCC33155, Legionella pneumophilia subsp. pneumophilia ATCC33215, andLegionella pneumophilia subsp. fraseri ATCC33216), Mycoplasma pneumoniae(Mycoplasma pneumoniae ATCC15531), and the like.

The compound of the general formula [1] of the present invention hasexcellent safety. The safety can be evaluated by various tests, forexample, by various types of safety tests selected from a cytotoxicitytest, a selectivity test against DNA gyrase of human and variousbacteria, a selectivity test against topoisomerase IV of human andvarious bacteria, an hERG test, a repeat-dose toxicity test, acytochrome P450 (CYP) activity inhibition test, a metabolic dependenceinhibition test, an in vivo mouse micronucleus test, an in vivo ratliver UDS test, and the like.

The compound of the general formula [1] of the present invention hasexcellent metabolic stability. The metabolic stability can be evaluatedby various tests, for example, by various types of stability testsselected from a human liver microsome metabolic stability test, a humanS9 stability test, and the like.

In particular, the compounds in Examples 2, 4, 77 and 85 of the presentinvention exhibited higher antimicrobial activity and safety and furtherhigher metabolic stability and tissue distribution.

Furthermore, usefulness of the compounds of the general formula [1] ofthe present invention will now be described with reference to thefollowing test examples.

TEST EXAMPLE 1 Susceptibility Test 1

Test substances were initially dissolved in dimethylsulfoxide.Antibacterial activities (MICs) of the same compounds were determined bythe micro-dilution method as recommended by the Japanese Society ofChemotherapy.

Staphylococcus aureus (S. aureus FDA209P, F-3095) was used as the testorganism. The bacteria cultured on Mueller-Hinton agar (MHA) plates at35° C. overnight were suspended in sterile physiological saline in aconcentration that was equivalent to 0.5 McFarland. The bacterialinoculum was prepared by 10-fold dilution of this suspension.Approximately 0.005 mL of the bacterial inoculum was inoculated intoCation-adjusted Mueller-Hinton broth (CAMHB, 100 μL/well) containing thetest substance and was incubated at 35° C. overnight. The lowestconcentration of the test substance at which no bacterial growth wasmacroscopically observed was determined as the MIC. Table 6 shows theresults.

TABLE 6 Test substance MIC (μg/mL) (Example No.) S. aureus FDA209P S.aureus F-3095  2 0.0313 0.0313  4 0.0313 0.0313  8 0.0313 0.0313  100.0156 0.0156  17 0.0039 0.0313  30 0.0313 0.0313  33 0.0313 0.0313  350.0313 0.0313  44 0.0313 0.0313  45 0.0313 0.0625  55 0.0039 0.0078  770.0313 0.0625  79 0.0078 0.0156  80 0.0078 0.0156  85 0.0313 0.0313  900.0313 0.0313  93 0.0625 0.0313  95 0.0313 0.0625  96 0.0625 0.0625 1030.0625 0.0625 118 0.0625 0.0625 119B 0.0625 0.0625 123 0.0313 0.125 1330.0078 0.0156 137 0.0313 0.0625 140 0.0156 0.0156 141 0.0313 0.0313 1430.0313 0.0313 144 0.0313 0.0313 146 0.0625 0.0625 147 0.0313 0.0625 1490.0313 0.0313 151 0.0313 0.125 152 0.0625 0.0625 162 0.0313 0.0625 1630.0313 0.0313

TEST EXAMPLE 2 S. aureus Infection Experiment

ICR mice (male, SPF grade, 4-week old, five mice per group) were used. Abacterial inoculum was prepared by suspending Staphylococcus aureus (S.aureus Smith), which was cultured on a Mueller-Hinton agar plate at 37°C. overnight, in sterile physiological saline, preparing a bacterialsolution of about 4×10⁸ CFU/mL, and diluting the solution 10-fold in5.6% mucin-phosphate buffer. ICR mice were intraperitoneallyadministered with the bacterial inoculum (approximately 2×10⁷ CFU/mouse)to induce infection. Test substances were dissolved in 10%hydroxypropyl-β-cyclodextrin and 0.05 mol/L hydrochloric acid. Each ofthe test substance solutions was subcutaneously administered once in anamount of 3 mg/kg to the mice after 1 hour of the infection. The numberof surviving mice was recorded on 5 days after the infection.

As the result, all mice of the control group which were not administeredwith the test substance died. However, all mice of the administrationgroups of Example Nos. 2, 4, 68, 77, 93, 103, 119B, 140, 149 and 151survived. Similarly, the compound of Example 85 was administered in anamount of 1 mg/kg. As the result, four mice out of five survived.

TEST EXAMPLE 3 Cytotoxicity Test

Each test substance was dissolved in dimethyl sulfoxide and was preparedto each concentration with E-MEM containing 10% FBS, and then 0.1 mL ofthis solution was dispensed into each well of a 96-well microplate. Avero cell suspension containing 3×10⁴ cells/mL was prepared with E-MEMcontaining 10% FBS, and 0.1 mL of the suspension was inoculated to eachwell. After incubation in 5% CO₂ at 37° C. for 3 days, 50 μL of E-MEMcontaining 1 mg/mL of2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)carbonyl]-2H-tetrazolium,inner salt, monosodium salt (XTT) and 25 μM of phenazine methosulfate(PMS) was added to each well. After about 2 hours, the absorbance at 450nm was measured with a microplate reader.

The absorbance ratio of each well supplied with the test substance andthe control not containing the test substance was calculated, and theconcentration of each compound when cell proliferation was inhibited by50% (CC₅₀; μg/mL) was calculated.

As the result, the CC₅₀ values of all compounds of Example Nos. 2, 4, 8,10, 30, 33, 35, 55, 68, 77, 79, 80, 85, 90, 93, 95, 96 and 103 were 51.2μg/mL or more.

The present invention will be then described with reference to ReferenceExamples and Examples; however, the present invention is not limited tothese Examples.

Unless otherwise stated, the carrier used in silica gel columnchromatography is B. W. silica gel, BW-127ZH, manufactured by FujiSilysia Chemical Ltd.; the carrier used in basic silica gel columnchromatography is silica gel, FL100D, manufactured by Fuji SilysiaChemical Ltd.; and the carrier used in reversed phase silica gel columnchromatography is ODS-AM120-S50, manufactured by YMC Co., Ltd.

Flash column chromatography is performed with a medium pressure liquidchromatograph, YFLC-Wprep2XY. N, manufactured by YAMAZEN CORPORATION.Unless otherwise stated, a silica gel column is a Hi-Flash column, W001,W002, W003 or W004, manufactured by YAMAZEN CORPORATION; and a basicsilica gel column is a Hi-Flash column, W091, W092 or W093, manufacturedby YAMAZEN CORPORATION.

A mixing ratio for an eluent is indicated as a volume ratio.

In Examples, respective abbreviations stand for the following meanings:

Ac: acetyl, Boc: tert-butoxycarbonyl, Bu: butyl, Et: ethyl, Me: methyl,MOM: methoxymethyl, Tf: trifluoromethylsulfonyl, THP:tetrahydro-2H-pyran-2-yl, Z: benzyloxycarbonyl, and DMSO-d₆: deuterateddimethylsulfoxide.

REFERENCE EXAMPLE 1

To 1.0 g of 2-chloro-5-methoxypyridin-3-amine, 0.82 mL of ethylacrylate, 4.2 mL of triethylamine, and 0.16 g ofbis(tri-tert-butylphosphine)palladium(0) were added, and the mixture wasstirred at an external temperature of 150 to 160° C. for 6 hours in asealed tube. The reaction mixture was cooled to room temperature and thesolvent was distilled off under reduced pressure. The resultant residuewas purified by flash silica gel column chromatography using gradientelution with chloroform:methanol=100:0 to 90:10 to obtain 0.41 g ofethyl (2E)-3-(3-amino-5-methoxypyridin-2-yl)acrylate and 0.25 g of7-methoxy-1,5-naphthyridin-2(1H)-one as light brown solids.

Ethyl (2E)-3-(3-amino-5-methoxypyridin-2-yl)acrylate

¹H-NMR (CDCl₃) δ: 1.32 (3H, t, J=7.2 Hz), 3.83 (3H, s), 3.96-4.04 (2H,m), 4.25 (2H, q, J=7.2 Hz), 6.46 (1H, d, J=2.7 Hz), 6.78 (1H, d, J=15.1Hz), 7.74 (1H, d, J=15.1 Hz), 7.83 (1H, d, J=2.7 Hz)

7-methoxy-1,5-naphthyridin-2(1H)-one

¹H-NMR (DMSO-d₆) δ: 3.88 (3H, s), 6.54 (1H, d, J=9.8 Hz), 7.13 (1H, d,J=2.6 Hz), 7.86 (1H, d, J=9.8 Hz), 8.21 (1H, d, J=2.6 Hz), 11.78 (1H, s)

REFERENCE EXAMPLE 2

To a solution of 0.51 g of ethyl(2E)-3-(3-amino-5-methoxypyridin-2-yl)acrylate in 6 mL of methanol, 0.53g of a 28% sodium methoxide/methanol solution was added at roomtemperature, and the mixture was heated under reflux while stirring for2 hours 20 minutes. Thereto was added 0.53 g of a 28% sodiummethoxide/methanol solution, and the mixture was heated under refluxwhile stirring for 1 hour 45 minutes. Thereto was further added 0.53 gof a 28% sodium methoxide/methanol solution, and the mixture was heatedunder reflux while stirring for 1 hour 15 minutes. The reaction mixturewas cooled to room temperature, the solvent was then distilled off underreduced pressure, and the resultant residue was charged with ethylacetate and water and adjusted to pH 7.2 with 1 mol/L hydrochloric acid.The solvent was distilled off under reduced pressure, and the solid wasfiltered off and washed with water and diethyl ether to obtain 0.25 g of7-methoxy-1,5-naphthyridin-2(1H)-one as a light brown solid.

REFERENCE EXAMPLE 3

To a suspension of 0.23 g of 7-methoxy-1,5-naphthyridin-2(1H)-one in 3mL of N,N-dimethylformamide, 79 mg of 60% sodium hydride was added atroom temperature, the temperature was increased to 50° C., and themixture was stirred for 15 minutes. Thereto was added 0.41 mL of2-bromomethyl-1,3-dioxolan, the temperature of the reaction mixture wasincreased to 90 to 100° C., and the reaction mixture was stirred for 3hours. The reaction mixture was cooled to room temperature, and waterand ethyl acetate were added thereto. The organic layer was separated,and the aqueous layer was extracted with ethyl acetate. The organiclayer and the extract were combined, the resultant solution was driedover anhydrous magnesium sulfate, and the solvent was distilled offunder reduced pressure. The resultant residue was purified by flashsilica gel column chromatography using gradient elution withhexane:ethyl acetate=100:0 to 33:67, then gradient elution withchloroform:methanol=100:0 to 90:10 to obtain 0.11 g of1-(1,3-dioxolan-2-ylmethyl)-7-methoxy-1,5-naphthyridin-2(1H)-one as alight brown solid.

¹H-NMR (CDCl₃) δ: 3.83-4.07 (4H, m), 3.97 (3H, s), 4.50 (2H, d, J=4.1Hz), 5.20 (1H, t, J=4.1 Hz), 6.77 (1H, d, J=9.8 Hz), 7.40 (1H, d, J=2.4Hz), 7.86 (1H, d, J=9.8 Hz), 8.28 (1H, d, J=2.4 Hz)

REFERENCE EXAMPLE 4

To 0.11 g of1-(1,3-dioxolan-2-ylmethyl)-7-methoxy-1,5-naphthyridin-2(1H)-one, 6.0 mLof an 80% aqueous trifluoroacetic acid solution was added, and themixture was stirred at 60 to 70° C. for 1 hour. Thereto was added 4.0 mLof an 80% aqueous trifluoroacetic acid solution, and the mixture wasstirred at 60 to 70° C. for 1 hour. The reaction mixture was cooled toroom temperature, and the solvent was distilled off under reducedpressure. The resultant residue was charged with ethyl acetate and waterand adjusted to pH 7.0 with a 1 mol/L aqueous sodium hydroxide solution.The organic layer was separated, and the aqueous layer was extractedwith ethyl acetate. The organic layer and the extract were combined andthe resultant solution was dried over anhydrous magnesium sulfate, andthe solvent was distilled off under reduced pressure to obtain 0.11 g of(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde as a light brownfoam.

¹H-NMR (DMSO-d₆) δ: 3.92 (3H, s), 5.28 (2H, s), 6.70 (1H, d, J=9.6 Hz),7.36 (1H, d, J=2.4 Hz), 7.94 (1H, d, J=9.6 Hz), 8.29 (1H, d, J=2.4 Hz),9.68 (1H, s)

REFERENCE EXAMPLE 5

To 0.99 g of 2-bromo-5-fluoropyridin-3-amine, 0.67 mL of ethyl acrylate,3.5 mL of triethylamine, and 0.13 g ofbis(tri-tert-butylphosphine)palladium(0) were added, and the mixture wasstirred at an external temperature of 145 to 150° C. for 5 hours in asealed tube. The reaction mixture was cooled to room temperature and thesolvent was distilled off under reduced pressure. The resultant residuewas purified by flash silica gel column chromatography using gradientelution with chloroform:methanol=100:0 to 90:10 to obtain 0.37 g ofethyl (2E)-3-(3-amino-5-fluoropyridin-2-yl)acrylate and 0.15 g of7-fluoro-1,5-naphthyridin-2(1H)-one as light brown solids.

Ethyl (2E)-3-(3-amino-5-fluoropyridin-2-yl)acrylate

¹H-NMR (CDCl₃) δ: 1.33 (3H, t, J=7.1 Hz), 4.02-4.12 (2H, broad), 4.27(2H, q, J=7.1 Hz), 6.71 (1H, dd, J=9.8, 2.4 Hz), 6.85 (1H, d, J=15.1Hz), 7.71 (1H, d, J=15.1 Hz), 7.94 (1H, d, J=2.4 Hz)

7-fluoro-1,5-naphthyridin-2(1H)-one

¹H-NMR (DMSO-d₆) δ: 6.72 (1H, dd, J=9.8, 1.7 Hz), 7.47 (1H, dd, J=9.6,2.5 Hz), 7.94 (1H, d, J=9.8 Hz), 8.50 (1H, d, J=2.5 Hz), 11.99 (1H, s)

REFERENCE EXAMPLE 6

To a solution of 0.36 g of ethyl(2E)-3-(3-amino-5-fluoropyridin-2-yl)acrylate in 3 mL of methanol, 0.37g of a 28% sodium methoxide/methanol solution was added at roomtemperature, and the mixture was heated under reflux while stirring for2 hours 40 minutes. Thereto was added 72 mg of a 28% sodiummethoxide/methanol solution, and the mixture was heated under refluxwhile stirring for 1 hour. The reaction mixture was cooled to roomtemperature, the solvent was then distilled off under reduced pressure,and the resultant residue was charged with ethyl acetate and water andadjusted to pH 6.7 with 1 mol/L hydrochloric acid. The solvent wasdistilled off under reduced pressure, the solid was filtered off andwashed with water and diethyl ether to obtain 0.17 g of7-fluoro-1,5-naphthyridin-2(1H)-one as a light brown solid.

¹H-NMR (DMSO-d₆) δ: 6.72 (1H, d, J=9.8 Hz), 7.47 (1H, dd, J=9.6, 2.4Hz), 7.94 (1H, d, J=9.8 Hz), 8.50 (1H, d, J=2.4 Hz), 11.99 (1H, brs)

REFERENCE EXAMPLE 7

To a suspension of 0.32 g of 7-fluoro-1,5-naphthyridin-2(1H)-one in 3 mLof N,N-dimethylformamide, 0.12 g of 60% sodium hydride was added at roomtemperature, and the mixture was stirred at 50 to 60° C. for 1 hour.Thereto was added 0.60 mL of 2-bromomethyl-1,3-dioxolan, the temperaturewas increased to 85 to 95° C., and the reaction mixture was stirred for4 hours. The reaction mixture was cooled to room temperature, and waterand ethyl acetate were then added thereto. The organic layer wasseparated, and the aqueous layer was extracted with ethyl acetate. Theorganic layer and the extract were combined, the resultant solution wasdried over anhydrous magnesium sulfate, and the solvent was distilledoff under reduced pressure. To the resultant residue, chloroform wasadded, the solid was filtered off and purified by flash silica gelcolumn chromatography using gradient elution with hexane:ethylacetate=100:0 to 30:70 to obtain 0.23 g of1-(1,3-dioxolan-2-ylmethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one as alight yellow solid.

¹H-NMR (CDCl₃) δ: 3.84-3.93 (2H, m), 3.96-4.05 (2H, m), 4.45 (2H, d,J=4.2 Hz), 5.19 (1H, t, J=4.2 Hz), 6.88 (1H, d, J=9.8 Hz), 7.69 (1H, dd,J=10.5, 2.4 Hz), 7.90 (1H, d, J=9.8 Hz), 8.41 (1H, d, J=2.4 Hz)

REFERENCE EXAMPLE 8

To 0.21 g of1-(1,3-dioxolan-2-ylmethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one, 3 mL ofan 80% aqueous trifluoroacetic acid solution was added, and the mixturewas stirred at room temperature for 20 minutes, and then stirred at 50to 60° C. for 1 hour. Thereto was added 3 mL of an 80% aqueoustrifluoroacetic acid solution, the mixture was stirred at 80 to 90° C.for 1 hour 45 minutes, then, 3 mL of an 80% aqueous trifluoroacetic acidsolution was further added thereto, and the mixture was stirred at thesame temperature for 1 hour. The reaction mixture was cooled to roomtemperature, and the solvent was then distilled off under reducedpressure. The resultant residue was charged with chloroform and waterand adjusted to pH 7.4 with a 20% aqueous sodium hydroxide solution. Theorganic layer was separated, and the aqueous layer was extracted withchloroform. The organic layer and the extract were combined, theresultant solution was dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure to obtain 0.20 g of7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde as a yellow oilysubstance.

¹H-NMR (CDCl₃) δ: 5.12 (2H, s), 6.93 (1H, d, J=9.9 Hz), 7.04 (1H, dd,J=9.6, 2.3 Hz), 7.98 (1H, d, J=9.9 Hz), 8.46 (1H, d, J=2.3 Hz), 9.77(1H, s)

REFERENCE EXAMPLE 9

By the same technique as in Reference Example 21, 0.22 g of (A)1-benzyl-N-(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)-2-methylpiperidin-4-amineas a colorless oily substance and 0.13 g of (B)1-benzyl-N-(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)-2-methylpiperidin-4-amineas a colorless oily substance were obtained from 0.24 g of1-benzyl-2-methylpiperidin-4-one and 0.20 g of1-(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-yl)methanamine.

(A) ¹H-NMR (CDCl₃) δ: 1.07 (3H, d, J=6.6 Hz), 1.40-1.85 (4H, m),2.40-2.60 (2H, m), 2.80-3.00 (2H, m), 3.42 (1H, d, J=13.7 Hz), 3.69-3.82(3H, m), 4.24-4.35 (4H, m), 6.83 (1H, s), 7.18-7.36 (5H, m), 8.10 (1H,s) (B) ¹H-NMR (CDCl₃) δ: 1.19-1.40 (2H, m), 1.22 (3H, d, J=6.1 Hz),1.76-1.84 (1H, m), 1.86-1.97 (2H, m), 2.20-2.30 (1H, m), 2.40-2.55 (1H,m), 2.75-2.85 (1H, m), 3.14 (1H, d, J=13.5 Hz), 3.78 (2H, s), 4.07 (1H,d, J=13.5 Hz), 4.24-4.34 (4H, m), 6.81 (1H, s), 7.20-7.40 (5H, m), 8.09(1H, s)

REFERENCE EXAMPLE 10

By the same technique as in Reference Example 61, tert-butyl(1-benzyl-2-methylpiperidin-4-yl)(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)carbamatewas obtained from1-benzyl-N-(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)-2-methylpiperidin-4-amine.

¹H-NMR (CDCl₃) δ: 1.00-1.13 (3H, m), 1.35-1.65 (12H, s), 1.78-1.92 (1H,m), 2.48-2.60 (2H, m), 3.09-3.20 (1H, m), 3.48 (1H, d, J=13.5 Hz), 3.59(1H, d, J=13.5 Hz), 4.20-4.66 (7H, m), 6.73 (1H, s), 7.20-7.30 (5H, m),8.05 (1H, s)

REFERENCE EXAMPLE 11

To a suspension of 6.0 g of 1,7-naphthyridin-2(1H)-one in 60 mL ofN,N-dimethylformamide, 2.5 g of 60% sodium hydride was added at roomtemperature, and the mixture was stirred at 50 to 60° C. for 1 hour.Thereto was added 6.4 mL of 2-bromomethyl-1,3-dioxolan, the temperaturewas increased to 90 to 95° C., and the reaction mixture was stirred for2 hours 30 minutes. The temperature was further increased to 95 to 100°C., and the mixture was stirred for 4 hours. Thereto were added 0.82 gof 60% sodium hydride and 2.1 mL of 2-bromomethyl-1,3-dioxolan and themixture was further stirred at the same temperature for 2 hours. Theretowere added 0.49 g of 60% sodium hydride and 1.3 mL of2-bromomethyl-1,3-dioxolan and the mixture was stirred at 90 to 100° C.for 2 hours. Thereto were further added 0.49 g of 60% sodium hydride and1.3 mL of 2-bromomethyl-1,3-dioxolan and the mixture was stirred at thesame temperature for 4 hours. The reaction mixture was cooled to 5° C.,and ethyl acetate and ice water were then added thereto. The organiclayer was separated, and the aqueous layer was extracted with ethylacetate. The organic layer and the extract were combined, the resultantsolution was dried over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure. The resultant residue was purifiedby flash silica gel column chromatography using gradient elution withhexane:ethyl acetate=100:0 to 0:100 and then, using gradient elutionwith chloroform:methanol=100:0 to 90:10 to obtain 3.1 g of1-(1,3-dioxolan-2-ylmethyl)-1,7-naphthyridin-2(1H)-one as a brown solid.

¹H-NMR (CDCl₃) δ: 3.85-3.94 (2H, m), 3.99-4.08 (2H, m), 4.58 (2H, d,J=4.5 Hz), 5.29 (1H, t, J=4.5 Hz), 6.91 (1H, d, J=9.4 Hz), 7.41 (1H, d,J=5.1 Hz), 7.67 (1H, d, J=9.4 Hz), 8.45 (1H, d, J=5.1 Hz), 9.05 (1H, s)

REFERENCE EXAMPLE 12

(1) To 3.1 g of 1-(1,3-dioxolan-2-ylmethyl)-1,7-naphthyridin-2(1H)-one,30 mL of an 80% aqueous trifluoroacetic acid solution was added, and themixture was stirred at 70 to 80° C. for 2 hours. The reaction mixturewas cooled to room temperature, then 30 mL of an 80% aqueoustrifluoroacetic acid solution was added thereto, the mixture was stirredat 70 to 80° C. for 3 hours 30 minutes, and the temperature wasincreased to 75 to 85° C. and the mixture was stirred for 2 hours.Thereto was further added 30 mL of an 80% aqueous trifluoroacetic acidsolution, and the mixture was stirred at 80 to 90° C. for 2 hours 30minutes. The reaction mixture was cooled to room temperature, and thenleft overnight. The solvent was distilled off under reduced pressure,and the resultant residue was charged with chloroform and water andadjusted to pH 10.4 with a 20% aqueous sodium hydroxide solution. Sodiumchloride was added thereto, the organic layer was separated, and theaqueous layer was extracted with chloroform. The organic layer and theextract were combined, the resultant solution was dried over anhydrousmagnesium sulfate, and the solvent was distilled off under reducedpressure to obtain 2.5 g of(2-oxo-1,7-naphthyridin-1(2H)-yl)acetaldehyde as a yellow oilysubstance.

(2) To a solution of 2.5 g of(2-oxo-1,7-naphthyridin-1(2H)-yl)acetaldehyde in 25 mL ofdichloromethane, 2.6 g of tert-butyl (piperidin-4-yl) carbamate and 0.76mL of acetic acid, and 4.2 g of sodium triacetoxyborohydride were added,and the mixture was stirred at room temperature for 4 hours and thenleft overnight. Thereto was added chloroform and the reaction mixturewas adjusted to pH 9.1 with a saturated aqueous sodium hydrogencarbonate solution and a 20% aqueous sodium hydroxide solution. Theorganic layer was separated, and the aqueous layer was extracted withchloroform. The organic layer and the extract were combined, and theresultant solution was washed sequentially with water and a saturatedaqueous sodium chloride solution and dried over anhydrous magnesiumsulfate, and the solvent was distilled off under reduced pressure. Tothe resultant residue, diethyl ether was added, and the solid wasfiltered off to obtain 2.8 g of tert-butyl(1-(2-(2-oxo-1,7-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate asa slightly yellow solid.

¹H-NMR (CDCl₃) δ: 1.35-1.51 (2H, m), 1.44 (9H, s), 1.89-1.98 (2H, m),2.23-2.32 (2H, m), 2.67-2.74 (2H, m), 2.90-2.98 (2H, m), 3.41-3.55 (1H,m), 4.37-4.50 (3H, m), 6.89 (1H, d, J=9.5 Hz), 7.42 (1H, d, J=5.0 Hz),7.65 (1H, d, J=9.5 Hz), 8.45 (1H, d, J=5.0 Hz), 8.89 (1H, s)

REFERENCE EXAMPLE 13

To a solution of 2.8 g of tert-butyl(1-(2-(2-oxo-1,7-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate in20 mL of ethanol, 60 mL of a 6.2 mol/L hydrogen chloride/ethanolsolution was added at room temperature, and the mixture was stirred for2 hours. Thereto was further added 60 mL of a 6.2 mol/L hydrogenchloride/ethanol solution, and the mixture was stirred for 4 hours andthen left for 4 days. The solvent was distilled off under reducedpressure, diethyl ether was added to the resultant residue, and thesolid was filtered off to obtain 2.8 g of1-(2-(4-aminopiperidin-1-yl)ethyl)-1,7-naphthyridin-2(1H)-one as ayellow solid.

¹H-NMR (D₂O) δ: 1.94-2.09 (2H, m), 2.36-2.45 (2H, m), 3.23-3.37 (2H, m),3.54-3.70 (3H, m), 3.92-4.03 (2H, m), 4.81-4.87 (2H, m), 7.25 (1H, d,J=9.6 Hz), 8.20 (1H, d, J=9.6 Hz), 8.27 (1H, d, J=5.9 Hz), 8.64 (1H, d,J=5.9 Hz), 9.18 (1H, s)

REFERENCE EXAMPLE 14

To a solution of 1.1 g of 1-(1,3-dioxolan-2-yl)methanamine in 10 mL ofN,N-dimethylformamide, 1.6 mL of triethylamine and 2.0 g of2-chloro-6-methoxy-3-nitropyridine were added at room temperature, andthe mixture was stirred at 55 to 65° C. for 1 hour. The reaction mixturewas cooled to room temperature, and ethyl acetate and water were thenadded thereto. The organic layer was separated, and the aqueous layerwas extracted with ethyl acetate. The organic layer and the extract werecombined, the resultant solution was washed sequentially with water anda saturated aqueous sodium chloride solution and dried over anhydrousmagnesium sulfate, and the solvent was distilled off under reducedpressure to obtain 2.7 g ofN-(1,3-dioxolan-2-ylmethyl)-6-methoxy-3-nitropyridin-2-amine as a yellowsolid.

¹H-NMR (CDCl₃) δ: 3.90 (2H, dd, J=5.6, 3.5 Hz), 3.92-3.99 (2H, m), 3.97(3H, s), 4.01-4.10 (2H, m), 5.17 (1H, t, J=3.5 Hz), 6.07 (1H, d, J=9.1Hz), 8.31 (1H, d, J=9.1 Hz), 8.76-8.85 (1H, broad)

REFERENCE EXAMPLE 15

To a solution of 2.7 g ofN-(1,3-dioxolan-2-ylmethyl)-6-methoxy-3-nitropyridin-2-amine in 30 mL ofethanol, 0.81 g of 10% palladium-carbon was added at room temperature,and mixture was stirred at 40° C. for 2 hours 30 minutes under ahydrogen atmosphere. The reaction mixture was cooled to roomtemperature, the insoluble substance was filtered off, and thefiltration residue was washed with diethyl ether. The solvent wasdistilled off under reduced pressure to obtain 2.4 g of3-amino-2-(1,3-dioxolan-2-ylmethyl)amino-6-methoxypyridine as a purplesolid.

¹H-NMR (CDCl₃) δ: 2.30-2.80 (2H, broad), 3.62-3.76 (2H, m), 3.84 (3H,s), 3.86-4.08 (4H, m), 4.30-5.10 (1H, broad), 5.15 (1H, t, J=4.4 Hz),5.93 (1H, d, J=7.8 Hz), 6.91 (1H, d, J=7.8 Hz)

REFERENCE EXAMPLE 16

To a solution of 0.20 g of3-amino-2-(1,3-dioxolan-2-ylmethyl)amino-6-methoxypyridine in 2 mL ofdioxane, 0.22 g of a 45 to 50% toluene solution of ethyl oxoacetate wasadded, and the mixture was stirred at room temperature for 2 hours andthen left overnight. Thereto was added 36 mg of 60% sodium hydride, andthe mixture was stirred at room temperature for 30 minutes. To thereaction mixture, water and ethyl acetate were added. The organic layerwas separated and the aqueous layer was extracted with ethyl acetate.The organic layer and the extract were combined, the resultant solutionwas washed with a saturated aqueous sodium chloride solution and driedover anhydrous magnesium sulfate, and the solvent was distilled offunder reduced pressure. The resultant residue was purified by flashsilica gel column chromatography using gradient elution withhexane:ethyl acetate=100:0 to 50:50 to obtain 36 mg of4-(1,3-dioxolan-2-ylmethyl)-6-methoxypyrido (2,3-b)pyrazin-3(4H)-one asa light brown solid.

¹H-NMR (CDCl₃) δ: 3.87-3.96 (2H, m), 4.04 (3H, s), 4.06-4.15 (2H, m),4.60 (2H, d, J=5.1 Hz), 5.57 (1H, t, J=5.1 Hz), 6.73 (1H, d, J=8.8 Hz),8.01 (1H, d, J=8.8 Hz), 8.18 (1H, s)

REFERENCE EXAMPLE 17

To 0.21 g of4-(1,3-dioxolan-2-ylmethyl)-6-methoxypyrido(2,3-b)pyrazin-3(4H)-one, 10mL of an 80% aqueous trifluoroacetic acid solution was added, and themixture was stirred at room temperature for 5 hours and then leftovernight. The solvent was distilled off under reduced pressure. Theresultant residue was charged with ethyl acetate and water and adjustedto pH 7.0 with a 1 mol/L aqueous sodium hydroxide solution. The organiclayer was separated, and the aqueous layer was extracted with ethylacetate. The organic layer and the extract were combined, the resultantsolution was dried over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure to obtain 0.18 g of(6-methoxy-3-oxopyrido(2,3-b)pyrazin-4(3H)-yl)acetaldehyde as a lightbrown foam.

¹H-NMR (CDCl₃) δ: 3.94 (3H, s), 5.22 (2H, s), 6.76 (1H, d, J=8.8 Hz),8.07 (1H, d, J=8.8 Hz), 8.24 (1H, s), 9.70 (1H, s)

REFERENCE EXAMPLE 18

To a solution of 1.2 g of 1,8-naphthyridin-2(1H)-one in 18 mL ofN,N-dimethylformamide, 0.36 g of 60% sodium hydride was added, and themixture was stirred at 50 to 60° C. for 7 minutes. Thereto was added0.94 mL of 2-bromomethyl-1,3-dioxolan, and the mixture was stirred at 95to 105° C. for 3 hours. The reaction mixture was cooled to roomtemperature, water and ethyl acetate were then added thereto, and theorganic layer was separated. The aqueous layer was extracted with ethylacetate and chloroform. The organic layer and the extract were combined,the resultant solution was dried over anhydrous magnesium sulfate, andthe solvent was distilled off under reduced pressure. The resultantresidue was purified by silica gel column chromatography using an eluentof hexane:ethyl acetate=1:1 to obtain 1.2 g of1-(1,3-dioxolan-2-ylmethyl)-1,8-naphthyridin-2(1H)-one as a white solid.

¹H-NMR (CDCl₃) δ: 3.83-3.93 (2H, m), 3.95-4.17 (2H, m), 4.72 (1H, d,J=5.1 Hz), 5.56 (1H, t, J=5.1 Hz), 6.72 (1H, d, J=9.5 Hz), 7.17 (1H, dd,J=7.6, 4.7 Hz), 7.64 (1H, d, J=9.5 Hz), 7.86 (1H, dd, J=7.6, 1.8 Hz),8.57 (1H, dd, J=4.7, 1.8 Hz)

REFERENCE EXAMPLE 19

To 1.1 g of 1-(1,3-dioxolan-2-ylmethyl)-1,8-naphthyridin-2(1H)-one, 11mL of a 90% aqueous trifluoroacetic acid solution was added, and themixture was stirred at room temperature for 2 hours. Then, 1.1 mL ofwater was added thereto and the mixture was stirred for 13 hours, andthereto was further added 1.1 mL of water and the mixture was stirredfor 3 hours 30 minutes, and stirred at 50 to 70° C. for 1 hour 30minutes. The solvent was distilled off under reduced pressure, and tothe resultant residue, a saturated aqueous sodium hydrogen carbonatesolution, water and chloroform were added. The organic layer wasseparated, and the aqueous layer was extracted with chloroform. Theorganic layer and the extract were combined, the resultant solution waswashed with a saturated aqueous sodium chloride solution and dried overanhydrous magnesium sulfate, and the solvent was distilled off underreduced pressure to obtain 0.75 g of(2-oxo-1,8-naphthyridin-1(2H)-yl)acetaldehyde as a yellow solid.

¹H-NMR (CDCl₃) δ: 5.36 (2H, s), 6.80 (1H, d, J=9.5 Hz), 7.20 (1H, dd,J=7.6, 4.8 Hz), 7.72 (1H, d, J=9.5 Hz), 7.91 (1H, dd, J=7.6, 1.8 Hz),8.51 (1H, dd, J=4.8, 1.8 Hz), 9.72 (1H, s)

REFERENCE EXAMPLE 20

To a solution of 1.0 g of 1,6-naphthyridin-2(1H)-one in 10 mL ofN,N-dimethylformamide, 0.30 g of 60% sodium hydride was added, and themixture was stirred at 50 to 60° C. for 1 hour. Thereto was added 0.78mL of 2-bromomethyl-1,3-dioxolan, and the reaction mixture was stirredat 90 to 100° C. for 30 minutes. Thereto were further added 0.30 g of60% sodium hydride and 0.78 mL of 2-bromomethyl-1,3-dioxolan, and themixture was stirred at 90 to 108° C. for 5 hours 30 minutes. Thereaction mixture was cooled to room temperature, water and chloroformwere then added thereto, the organic layer was separated, and theaqueous layer was extracted with chloroform. The organic layer and theextract were combined, the resultant solution washed with a saturatedaqueous sodium chloride solution and dried over anhydrous magnesiumsulfate, and the solvent was distilled off under reduced pressure. Theresultant residue was purified by silica gel column chromatography usingan eluent of chloroform:methanol=100:1 to obtain 0.60 g of1-(1,3-dioxolan-2-ylmethyl)-1,6-naphthyridin-2(1H)-one as a yellowsolid.

¹H-NMR (CDCl₃) δ: 3.84-3.94 (2H, m), 3.98-4.07 (2H, m), 4.48 (2H, d,J=4.3 Hz), 5.23 (1H, t, J=4.3 Hz), 6.75 (1H, d, J=9.5 Hz), 7.47 (1H, d,J=6.2 Hz), 7.78 (1H, d, J=9.5 Hz), 8.58 (1H, d, J=6.2 Hz), 8.76 (1H, s)

REFERENCE EXAMPLE 21

To a solution of 0.29 g of (2-oxo-1,8-naphthyridin-1(2H)-yl)acetaldehydein 10 mL of methylene chloride, 0.30 g of tert-butyl(piperidin-4-yl)carbamate and 87 μL of acetic acid were added, themixture was stirred for 10 minutes, and to the reaction mixture, 0.48 gof sodium triacetoxyborohydride was then added and the mixture wasstirred at room temperature for 4 hours. Thereto were added water, asaturated aqueous sodium hydrogen carbonate solution and chloroform, theorganic layer was separated, and the aqueous layer was extracted withchloroform. The organic layer and the extract were combined, and theresultant solution was washed with a saturated aqueous sodium chloridesolution and dried over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure. The resultant residue was purifiedby silica gel column chromatography using an eluent ofchloroform:methanol=100:1 to obtain 0.27 g of tert-butyl(1-(2-(2-oxo-1,8-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate asa light brown oily substance.

¹H-NMR (CDCl₃) δ: 1.36-1.51 (11H, m), 1.88-1.96 (2H, m), 2.19-2.28 (2H,m), 2.66-2.72 (2H, m), 2.98-3.06 (2H, m), 3.41-3.56 (1H, m), 4.50-4.60(1H, m), 4.65-4.70 (2H, m), 6.74 (1H, d, J=9.5 Hz), 7.17 (1H, dd, J=7.7,4.8 Hz), 7.63 (1H, d, J=9.5 Hz), 7.86 (1H, dd, J=7.7, 1.8 Hz), 8.58 (1H,dd, J=4.8, 1.8 Hz)

REFERENCE EXAMPLE 22

To a solution of 0.26 g of tert-butyl(1-(2-(2-oxo-1,8-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate in4 mL of dichloromethane, 2 mL of trifluoroacetic acid was added, and themixture was stirred at room temperature for 2 hours. The solvent wasdistilled off under reduced pressure, water and diethyl ether was addedto the resultant residue, and the aqueous layer was separated and washedwith diethyl ether, and then, thereto was added a 20% aqueous sodiumhydroxide solution and the reaction mixture was adjusted to pH 13 to 14.Thereto were added dichloromethane and sodium chloride, the organiclayer was separated, and the aqueous layer was extracted with chloroformwhile being salted out. The organic layer and the extract were combined,the resultant solution was dried over anhydrous magnesium sulfate, andthe solvent was distilled off under reduced pressure to obtain 0.15 g of1-(2-(4-aminopiperidin-1-yl)ethyl)-1,8-naphthyridin-2(1H)-one as ayellow oily substance.

¹H-NMR (CDCl₃) δ: 1.31-1.43 (2H, m), 1.77-1.91 (4H, m), 2.13-2.22 (2H,m), 2.62-2.73 (3H, m), 3.03-3.10 (2H, m), 4.66-4.72 (2H, m), 6.74 (1H,d, J=9.4 Hz), 7.17 (1H, dd, J=7.6, 4.6 Hz), 7.63 (1H, d, J=9.4 Hz), 7.86(1H, dd, J=7.6, 1.9 Hz), 8.59 (1H, dd, J=4.6, 1.9 Hz)

REFERENCE EXAMPLE 23

To a solution of 1.2 g of 1,5-naphthyridin-2(1H)-one in 24 mL ofN,N-dimethylformamide, 0.82 g of 60% sodium hydride was added at 60° C.,and the mixture was stirred at the same temperature for 20 minutes, andthen stirred at 55 to 80° C. for 30 minutes. Thereto was added 1.3 mL of2-bromomethyl-1,3-dioxolan at 60° C., the temperature of the reactionmixture was increased to 100° C. over 4 hours, and to the reactionmixture, 2.3 g of potassium carbonate was added, and the mixture wasstirred at the same temperature for 3 hours. After leaving overnight,0.85 mL of 2-bromomethyl-1,3-dioxolan and 0.33 g of 60% sodium hydridewere added thereto, and the mixture was stirred at 70 to 75° C. for 1hour 30 minutes. The reaction mixture was cooled to room temperature,water, sodium chloride and chloroform were then added thereto, and theorganic layer was separated. The aqueous layer was extracted withchloroform. The organic layer and the extract were combined, theresultant solution was dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure. The resultant residuewas purified by silica gel column chromatography using an eluent ofchloroform:methanol=49:1 to obtain 1.1 g of1-(1,3-dioxolan-2-ylmethyl)-1,5-naphthyridin-2(1H)-one as a light yellowsolid.

¹H-NMR (CDCl₃) δ: 3.82-3.94 (2H, m), 3.96-4.05 (2H, m), 4.52 (2H, d,J=4.2 Hz), 5.22 (1H, t, J=4.2 Hz), 6.94 (1H, d, J=9.8 Hz), 7.45 (1H, dd,J=8.6, 4.5 Hz), 7.90-7.98 (2H, m), 8.54 (1H, dd, J=4.5, 1.2 Hz)

REFERENCE EXAMPLE 24

To 1.0 g of 1-(1,3-dioxolan-2-ylmethyl)-1,5-naphthylridin-2(1H)-one, 5mL of an 80% aqueous trifluoroacetic acid solution was added, and themixture was stirred at 60 to 70° C. for 30 minutes, and then stirred at70 to 90° C. for 4 hours. Thereto was further added 5 mL of an 80%aqueous trifluoroacetic acid solution, and the mixture was stirred for 2hours. The solvent was distilled off under reduced pressure, a saturatedaqueous sodium hydrogen carbonate solution, sodium chloride andchloroform were added to the resultant residue, and the organic layerwas separated, and the aqueous layer was extracted with chloroform. Theorganic layer and the extract were combined, the resultant solution wasdried over anhydrous magnesium sulfate, and the solvent was distilledoff under reduced pressure to obtain 0.73 g of(2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde as an orange oilysubstance.

¹H-NMR (CDCl₃) δ: 5.15 (2H, s), 6.99 (1H, d, J=10.0 Hz), 7.43-7.49 (1H,m), 7.96-8.03 (2H, m), 8.56-8.62 (1H, m), 9.76 (1H, s)

REFERENCE EXAMPLE 25

To a solution of 0.24 g of tert-butyl(1-benzyl-2-methylpiperidin-4-yl)(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)carbamatein 3 mL of methanol, 90 μL of acetic acid and 0.32 g of 20% palladiumhydroxide were added. The reaction mixture was stirred for 4 hours 30minutes under a hydrogen atmosphere. The insoluble substance wasfiltered off, and the solvent was distilled off under reduced pressureto obtain 0.16 g of tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(2-methylpiperidin-4-yl)carbamateas a yellow foam.

¹H-NMR (CDCl₃) δ: 1.36-1.45 (9H, m), 1.50 (3H, d, J=6.8 Hz), 1.67-1.75(1H, m), 1.86-1.95 (1H, m), 2.03-2.14 (1H, m), 2.18-2.30 (1H, m),3.04-3.17 (1H, m), 3.26-3.35 (1H, m), 3.83-3.93 (1H, m), 4.27-4.51 (7H,m), 6.71-6.83 (1H, m), 8.08 (1H, s), 9.40-9.60 (1H, m)

REFERENCE EXAMPLE 26

(1) By the same technique as in Reference Example 61, tert-butyl(1-benzyl-2-methylpiperidin-4-yl)(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)carbamatewas obtained from1-benzyl-N-(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)-2-methylpiperidin-4-amine.

(2) By the same technique as in Reference Example 25, tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(2-methylpiperidin-4-yl)carbamatewas obtained from tert-butyl(1-benzyl-2-methylpiperidin-4-yl)(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)carbamate.

¹H-NMR (CDCl₃) δ: 1.27-1.57 (14H, m), 1.82-2.00 (2H, m), 2.83-2.97 (1H,m), 3.14-3.27 (1H, m), 3.40-3.53 (1H, m), 4.26-4.61 (7H, m), 6.62-7.02(1H, m), 8.05-8.13 (1H, m), 9.84-10.06 (1H, m)

REFERENCE EXAMPLE 27

By the same technique as in Reference Example 3,1-(1,3-dioxolan-2-ylmethyl)pyrido(3,4-b)pyrazin-2(1H)-one was obtainedfrom pyrido(3,4-b)pyrazin-2(1H)-one and 2-bromomethyl-1,3-dioxolan.

¹H-NMR (CDCl₃) δ: 3.84-4.02 (4H, m), 4.44 (2H, d, J=4.0 Hz), 5.24 (1H,t, J=4.0 Hz), 7.43 (1H, d, J=6.0 Hz), 8.33 (1H, s), 8.63 (1H, d, J=6.0Hz), 9.07 (1H, s)

REFERENCE EXAMPLE 28

To a solution of 3.2 g of 7-chloro-1,8-naphthyridin-2(1H)-one in 32 mLof N,N-dimethylformamide, 3.7 g of potassium carbonate was added, andthe mixture was stirred at 50 to 60 C.° for 23 minutes, and then,thereto was added 2.2 mL of 2-bromomethyl-1,3-dioxolan, and the mixturewas stirred at 60 to 78° C. for 25 minutes. Thereto were added 16 mL ofN,N-dimethylformamide and 1.1 mL of 2-bromomethyl-1,3-dioxolan, themixture was stirred at 90 to 95° C. for 2 hours 15 minutes, 3.7 g ofpotassium carbonate was added thereto, and the mixture was stirred for20 minutes. The reaction mixture was cooled to room temperature, waterand ethyl acetate were then added thereto, the organic layer wasseparated, and the aqueous layer was extracted with ethyl acetate. Theorganic layer and the extract were combined, the resultant solution wasdried over anhydrous magnesium sulfate, and the solvent was distilledoff under reduced pressure. The resultant residue was purified by silicagel column chromatography using an eluent of hexane:ethyl acetate=1:1 toobtain 3.6 g of7-chloro-1-(1,3-dioxolan-2-ylmethyl)-1,8-naphthyridin-2(1H)-one as ayellow solid.

¹H-NMR (CDCl₃) δ: 3.86-3.96 (2H, m), 4.10-4.20 (2H, m), 4.63 (2H, t,J=5.4 Hz), 5.60 (1H, t, J=5.4 Hz), 6.75 (1H, d, J=9.6 Hz), 7.17 (1H, d,J=8.0 Hz), 7.62 (1H, d, J=9.6 Hz), 7.79 (1H, d, J=8.0 Hz)

REFERENCE EXAMPLE 29

To a solution of 2.5 g of7-chloro-1-(1,3-dioxolan-2-ylmethyl)-1,8-naphthyridin-2(1H)-one in 30 mLof methanol, 5.4 g of a 28% sodium methoxide/methanol solution wasadded, and the mixture was heated under reflux while stirring for 3hours 40 minutes. The reaction mixture was cooled to room temperature,then water was added thereto, and the solvent was then distilled offunder reduced pressure. To the resultant residue, water, a saturatedaqueous ammonium chloride solution and chloroform were added, theorganic layer was separated, and the aqueous layer was extracted withchloroform. The organic layer and the extract were combined, and theresultant solution was washed with a saturated aqueous sodium chloridesolution and dried over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure to obtain 2.9 g of1-(1,3-dioxolan-2-ylmethyl)-7-methoxy-1,8-naphthyridin-2(1H)-one as ayellow oily substance.

¹H-NMR (CDCl₃) δ: 3.84-3.94 (2H, m), 4.00 (3H, s), 4.05-4.15 (2H, m),4.65 (2H, d, J=5.1 Hz), 5.56 (1H, t, J=5.1 Hz), 6.55 (1H, d, J=9.3 Hz),6.57 (1H, d, J=8.6 Hz), 7.55 (1H, d, J=9.3 Hz), 7.69 (1H, d, J=8.6 Hz)

REFERENCE EXAMPLE 30

To 2.8 g of1-(1,3-dioxolan-2-ylmethyl)-7-methoxy-1,8-naphthyridin-2(1H)-one, 20 mLof an 80% aqueous trifluoroacetic acid solution was added, and themixture was stirred at 60 to 72° C. for 3 hours 20 minutes, and at 80 to85° C. for 2 hours 20 minutes, 4 mL of water was then added thereto andthe mixture was further stirred for 4 hours. The reaction mixture wascooled to room temperature and then left overnight, and the solvent wasdistilled off under reduced pressure. To the resultant residue, asaturated aqueous sodium hydrogen carbonate solution and chloroform wereadded, the organic layer was separated, and the aqueous layer wasextracted with chloroform. The organic layer and the extract werecombined, the resultant solution was dried over anhydrous magnesiumsulfate, and the solvent was distilled off under reduced pressure toobtain 1.8 g of (7-methoxy-2-oxo-1,8-naphthyridin-1(2H)-yl)acetaldehydeas a yellow solid.

¹H-NMR (CDCl₃) δ: 3.92 (3H, s), 5.23 (2H, d, J=0.7 Hz), 6.63-6.67 (2H,m), 7.66 (1H, d, J=9.5 Hz), 7.78 (1H, d, J=8.3 Hz), 9.65-9.67 (1H, m)

REFERENCE EXAMPLE 31

To a solution of 1.6 g of(7-methoxy-2-oxo-1,8-naphthyridin-1(2H)-yl)acetaldehyde in 70 mL ofdichloromethane, 1.5 g of tert-butyl (piperidin-4-yl) carbamate and 0.42mL of acetic acid were added, the mixture was stirred for 20 minutes,then 2.3 g of sodium triacetoxyborohydride was added to the reactionmixture and the mixture was stirred at room temperature for 2 hours 10minutes. Thereto were added water, a saturated aqueous sodium hydrogencarbonate solution and chloroform, the organic layer was separated, andthe aqueous layer was extracted with chloroform. The organic layer andthe extract were combined, the resultant solution was washed with asaturated aqueous sodium chloride solution and dried over anhydrousmagnesium sulfate, and the solvent was distilled off under reducedpressure. The resultant residue was purified by silica gel columnchromatography using an eluent of chloroform:methanol=50:1 to obtain 2.8g of tert-butyl(1-(2-(7-methoxy-2-oxo-1,8-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamateas a white foam.

¹H-NMR (CDCl₃) δ: 1.38-1.51 (11H, m), 1.88-1.98 (2H, m), 2.22-2.31 (2H,m), 2.69-2.75 (2H, m), 2.98-3.06 (2H, m), 3.41-3.52 (1H, m), 4.01 (3H,s), 4.38-4.47 (1H, m), 4.61-4.66 (2H, m), 6.57 (1H, d, J=9.3 Hz), 6.61(1H, d, J=8.5 Hz), 7.56 (1H, d, J=9.3 Hz), 7.72 (1H, d, J=8.5 Hz)

REFERENCE EXAMPLE 32

To 2.8 g of tert-butyl(1-(2-(7-methoxy-2-oxo-1,8-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate,50 mL of a 4 mol/L hydrogen chloride/ethyl acetate solution was added,and the mixture was stirred at room temperature for 29 hours. Thesolvent was distilled off under reduced pressure, ethyl acetate wasadded to the solid thus obtained, and a crystal was filtered off andwashed with ethyl acetate to obtain 2.3 g of1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,8-naphthyridin-2(1H)-onehydrochloride as a light yellow solid.

¹H-NMR (D₂O) δ: 1.90-2.05 (2H, m), 2.34-2.43 (2H, m), 3.17-3.30 (2H, m),3.55-3.67 (3H, m), 3.93-4.02 (2H, m), 4.04 (3H, s), 4.88-4.94 (2H, m),6.62 (1H, d, J=9.5 Hz), 6.83 (1H, d, J=8.5 Hz), 7.93 (1H, d, J=9.5 Hz),8.01 (1H, d, J=8.5 Hz)

REFERENCE EXAMPLE 33

By the same technique as in Reference Example 14,N-(1,3-dioxolan-2-ylmethyl)-3-nitropyridin-2-amine was obtained from2-bromo-3-nitropyridine and 1-(1,3-dioxolan-2-yl)methanamine.

¹H-NMR (CDCl₃) δ: 3.90-4.10 (6H, m), 5.17 (1H, t, J=3.4 Hz), 6.64-6.69(1H, m), 8.36-8.44 (3H, m)

REFERENCE EXAMPLE 34

By the same technique as in Reference Example 15,3-amino-2-(1,3-dioxolan-2-ylmethyl)aminopyridine was obtained fromN-(1,3-dioxolan-2-ylmethyl)-3-nitropyridin-2-amine.

¹H-NMR (CDCl₃) δ: 3.20-3.60 (2H, broad), 3.70-3.74 (2H, m), 3.87-4.08(4H, m), 4.76-4.88 (1H, broad), 5.16 (1H, t, J=4.1 Hz), 6.55 (1H, dd,J=7.4, 5.2 Hz), 6.86 (1H, dd, J=7.4, 1.3 Hz), 7.70 (1H, dd, J=5.2, 1.3Hz)

REFERENCE EXAMPLE 35

To a solution of 0.20 g of3-amino-2-(1,3-dioxolan-2-ylmethyl)aminopyridine in 2 mL of ethanol,0.25 g of a 45 to 50% toluene solution of ethyl oxoacetate was added,and the mixture was heated under reflux while stirring for 1 hour 30minutes. The reaction mixture was cooled to room temperature, andthereto were added water and ethyl acetate. The organic layer wasseparated and the aqueous layer was extracted with ethyl acetate. Theorganic layer and the extract were combined, the resultant solution waswashed with a saturated aqueous sodium chloride solution and dried overanhydrous magnesium sulfate, and the solvent was distilled off underreduced pressure. The resultant residue was purified by flash silica gelcolumn chromatography using gradient elution withchloroform:methanol=100:0 to 90:10 to obtain 0.16 g of4-(1,3-dioxolan-2-ylmethyl)pyrido(2,3-b)pyrazin-3(4H)-one as a lightbrown solid.

¹H-NMR (CDCl₃) δ: 3.85-3.95 (2H, m), 4.06-4.16 (2H, m), 4.66 (2H, d,J=5.2 Hz), 5.56 (1H, t, J=5.2 Hz), 7.33 (1H, dd, J=7.9, 4.7 Hz), 8.17(1H, dd, J=7.9, 1.7 Hz), 8.35 (1H, s), 8.60 (1H, dd, J=4.7, 1.7 Hz)

REFERENCE EXAMPLE 36

By the same technique as in Reference Example 4,(3-oxopyrido(2,3-b)pyrazin-4(3H)-yl)acetaldehyde was obtained from4-(1,3-dioxolan-2-ylmethyl)pyrido(2,3-b)pyrazin-3(4H)-one.

¹H-NMR (CDCl₃) δ: 5.33 (2H, s), 7.35 (1H, dd, J=7.9, 4.7 Hz), 8.22 (1H,dd, J=7.9, 1.7 Hz), 8.40 (1H, s), 8.52 (1H, dd, J=4.7, 1.7 Hz), 9.75(1H, s)

REFERENCE EXAMPLE 37

By the same technique as in Reference Example 42, tert-butyl(1-(2-(2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl) carbamatewas obtained from (2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde andtert-butyl (piperidin-4-yl)carbamate.

¹H-NMR (CDCl₃, D₂O) δ: 1.24-1.46 (11H, m), 1.90-1.98 (2H, m), 2.21-2.30(2H, m), 2.62-2.68 (2H, m), 2.88-2.97 (2H, m), 4.35-4.55 (3H, m), 6.92(1H, d, J=9.7 Hz), 7.47 (1H, dd, J=8.5, 4.5 Hz), 7.74-7.78 (1H, m), 7.92(1H, d, J=9.7 Hz), 8.55 (1H, dd, J=4.5, 1.1 Hz)

REFERENCE EXAMPLE 38

By the same technique as in Reference Example 13,1-(2-(4-aminopiperidin-1-yl)ethyl)1,5-naphthyridin-2(1H)-onehydrochloride was obtained from tert-butyl(1-(2-(2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl) carbamate.

¹H-NMR (D₂O) δ: 1.80-2.10 (2H, m), 2.26-2.48 (2H, m), 3.10-3.40 (2H, m),3.53-3.70 (3H, m), 3.90-4.10 (2H, m), 4.84-4.90 (2H, m), 7.31 (1H, d,J=10.0 Hz), 8.21 (1H, dd, J=9.0, 5.5 Hz), 8.26 (1H, d, J=10.0 Hz), 8.72(1H, d, J=9.0 Hz), 8.81 (1H, d, J=5.5 Hz)

REFERENCE EXAMPLE 39

To a suspension of 3.8 g of pyridine-2,3-diamine in 100 mL of dioxane,7.1 g of a 45 to 50% toluene solution of ethyl oxoacetate was added, andthe mixture was stirred at room temperature for 1 hour, and then heatedunder reflux while stirring for 1 hour. The reaction mixture was cooledwith ice bath, and diethyl ether was added thereto. The solid wasfiltered off to obtain 3.9 g of pyrido(2,3-b)pyrazin-2(1H)-one as alight brown solid.

¹H-NMR (DMSO-d₆) δ: 7.58 (1H, dd, J=8.2, 4.5 Hz), 7.73 (1H, dd, J=8.2,1.6 Hz), 8.37 (1H, s), 8.53 (1H, dd, J=4.5, 1.6 Hz)

REFERENCE EXAMPLE 40

By the same technique as in Reference Example 3,1-(1,3-dioxolan-2-ylmethyl)pyrido(2,3-b)pyrazin-2(1H)-one was obtainedfrom pyrido(2,3-b)pyrazin-2(1H)-one and 2-bromomethyl-1,3-dioxolan.

¹H-NMR (CDCl₃) δ: 3.83-4.00 (4H, m), 4.49 (2H, d, J=4.0 Hz), 5.23 (1H,t, J=4.0 Hz), 7.52 (1H, dd, J=8.5, 4.4 Hz), 7.99 (1H, dd, J=8.5, 1.5Hz), 8.56 (1H, s), 8.66 (1H, dd, J=4.4, 1.5 Hz)

REFERENCE EXAMPLE 41

By the same technique as in Reference Example 3,4-(1,3-dioxolan-2-ylmethyl)pyrido(3,4-b)pyrazin-3(4H)-one was obtainedfrom pyrido(3,4-b)pyrazin-3(4H)-one and 2-bromomethyl-1,3-dioxolan.

¹H-NMR (CDCl₃) δ: 3.85-4.05 (4H, m), 4.53 (2H, d, J=4.2 Hz), 5.29 (1H,t, J=4.2 Hz), 7.73 (1H, d, J=5.2 Hz), 8.49 (1H, s), 8.59 (1H, d, J=5.2Hz), 9.05 (1H, s)

REFERENCE EXAMPLE 42

To a solution of 0.18 g of(6-methoxy-3-oxopyrido(2,3-b)pyrazin-4(3H)-yl)acetaldehyde in 4 mL ofdichloromethane, 0.16 g of tert-butyl (piperidin-4-yl)carbamate and 47μL of acetic acid and 0.26 g of sodium triacetoxyborohydride were added,and the mixture was stirred at room temperature for 3 hours. Chloroformand a saturated aqueous sodium hydrogen carbonate solution were added tothe reaction mixture, the organic layer was separated, and the aqueouslayer was extracted with chloroform. The organic layer and the extractwere combined, the resultant solution was washed with a saturatedaqueous sodium chloride solution and dried over anhydrous magnesiumsulfate, and the solvent was distilled off under reduced pressure. Tothe resultant residue, diethyl ether, methanol and hexane were added,and the solid was filtered off to obtain 0.23 g of tert-butyl(1-(2-(6-methoxy-3-oxopyrido(2,3-b)pyrazin-4(3H)-yl)ethyl)piperidin-4-yl)carbamateas a light brown solid.

¹H-NMR (CDCl₃) δ: 1.25-1.47 (2H, m), 1.44 (9H, s), 1.86-1.95 (2H, m),2.18-2.28 (2H, m), 2.70-2.77 (2H, m), 2.93-3.02 (2H, m), 3.38-3.52 (1H,broad), 4.02 (3H, s), 4.35-4.44 (1H, m), 4.53-4.59 (2H, m), 6.73 (1H, d,J=8.8 Hz), 8.01 (1H, d, J=8.8 Hz), 8.15 (1H, s)

REFERENCE EXAMPLE 43

To a suspension of 0.23 g of tert-butyl(1-(2-(6-methoxy-3-oxopyrido(2,3-b)pyrazin-4(3H)-yl)ethyl)piperidin-4-yl)carbamatein 3 mL of ethyl acetate, 4.0 mL of a 4.0 mol/L hydrogen chloride/ethylacetate solution was added at room temperature. The mixture was stirredat the same temperature for 5 hours, and then left overnight. Thesolvent was distilled off under reduced pressure, diethyl ether wasadded to the resultant residue, and the solid was filtered off to obtain0.23 g of4-(2-(4-aminopiperidin-1-yl)ethyl)-6-methoxypyrido(2,3-b)pyrazin-3(4H)-onehydrochloride as a light brown solid.

¹H-NMR (D₂O) δ: 1.88-2.03 (2H, m), 2.32-2.43 (2H, m), 3.18-3.32 (2H, m),3.52-3.74 (3H, m), 3.91-4.04 (2H, m), 4.07 (3H, s), 4.87-4.93 (2H, m),6.98 (1H, d, J=8.9 Hz), 8.17 (1H, d, J=8.9 Hz), 8.18 (1H, s)

REFERENCE EXAMPLE 44

By the same technique as in Reference Example 1,7-methyl-1,5-naphthyridin-2(1H)-one was obtained from2-chloro-5-methylpyridin-3-amine and ethyl acrylate.

¹H-NMR (DMSO-d₆) δ: 2.39 (3H, s), 6.66 (1H, d, J=9.8 Hz), 7.43-7.47 (1H,m), 7.89 (1H, d, J=9.8 Hz), 8.32-8.34 (1H, m), 11.81-11.85 (1H, broad)

REFERENCE EXAMPLE 45

By the same technique as in Reference Example 3,1-(1,3-dioxolan-2-ylmethyl)-7-methyl-1,5-naphthyrdin-2(1H)-one wasobtained from 7-methyl-1,5-naphthyridin-2(1H)-one and2-bromomethyl-1,3-dioxolan.

¹H-NMR (CDCl₃) δ: 2.50 (3H, s), 3.84-3.93 (2H, m), 3.97-4.07 (2H, m),4.50 (2H, d, J=4.2 Hz), 5.22 (1H, t, J=4.2 Hz), 6.87 (1H, d, J=9.8 Hz),7.69-7.73 (1H, m), 7.89 (1H, d, J=9.8 Hz), 8.38 (1H, d, J=1.5 Hz)

REFERENCE EXAMPLE 46

By the same technique as in Reference Example 4,(7-methyl-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde was obtained from1-(1,3-dioxolan-2-ylmethyl)-7-methyl-1,5-naphthyrdin-2(1H)-one.

¹H-NMR (DMSO-d₆) δ: 2.41 (3H, s), 5.25 (2H, s), 6.83 (1H, d, J=9.8 Hz),7.73-7.78 (1H, m), 7.97 (1H, d, J=9.8 Hz), 8.38-8.42 (1H, m), 9.70 (1H,s)

REFERENCE EXAMPLE 47

By the same technique as in Reference Example 39,7-bromopyrido(2,3-b)pyrazin-2(1H)-one was obtained from5-bromopyridine-2,3-diamine and ethyl oxoacetate.

¹H-NMR (DMSO-d₆) δ: 7.86 (1H, d, J=2.2 Hz), 8.39 (1H, s), 8.60 (1H, d,J=2.2 Hz), 12.56-12.64 (1H, broad)

REFERENCE EXAMPLE 48

To a suspension of 4.0 g of 7-bromopyrido(2,3-b)pyrazin-2(1H)-one in 40mL of N,N-dimethylformamide, 8.2 g of a 28% sodium methoxide/methanolsolution and 0.25 g of copper (I) bromide were added at roomtemperature, and the mixture was stirred at 80 to 90° C. for 3 hoursunder a nitrogen atmosphere. The reaction mixture was cooled to 55° C.,thereto was added 2.8 mL of 2-bromomethyl-1,3-dioxolan, and the mixturewas stirred at 80 to 90° C. for 1 hour 30 minutes under a nitrogenatmosphere. The reaction mixture was cooled to room temperature and thenleft overnight. The mixture was further stirred at 80 to 90° C. for 1hour, and then stirred at 90 to 100° C. for 1 hour 30 minutes. Thereaction mixture was cooled to room temperature, and then ethyl acetateand water were added thereto. The insoluble substance was filtered off,the organic layer was separated, and the aqueous layer was extractedwith ethyl acetate. The organic layer and the extract were combined, theresultant solution was dried over anhydrous magnesium sulfate, and thesolvent was then distilled off under reduced pressure. The resultantresidue was purified by flash silica gel column chromatography usinggradient elution with chloroform:methanol=100:0 to 95:5, ethyl acetatewas added to the orange oily substance thus obtained, and the solid wasfiltered off to obtain 0.12 g of1-(1,3-dioxolan-2-ylmethyl)-7-methoxypyrido(2,3-b)pyrazin-2(1H)-one asan orange solid.

¹H-NMR (CDCl₃) δ: 3.84-3.93 (2H, m), 3.93-4.02 (2H, m), 3.99 (3H, s),4.47 (2H, d, J=3.8 Hz), 5.21 (1H, t, J=3.8 Hz), 7.39 (1H, d, J=2.7 Hz),8.36 (1H, d, J=2.7 Hz), 8.38 (1H, s)

REFERENCE EXAMPLE 49

By the same technique as in Reference Example 4,(7-methoxy-2-oxopyrido(2,3-b)pyrazin-1(2H)-yl)acetaldehyde was obtainedfrom1-(1,3-dioxolan-2-ylmethyl)-7-methoxypyrido(2,3-b)pyrazin-2(1H)-one.

¹H-NMR (DMSO-d₆) δ: 3.94 (3H, s), 5.31 (2H, s), 7.48 (1H, d, J=2.7 Hz),8.32 (1H, s), 8.33 (1H, d, J=2.7 Hz), 9.68 (1H, s)

REFERENCE EXAMPLE 50

To a solution of 0.50 g of 2,6-dichloro-3-nitropyridine in 5 mL ofacetonitrile, 0.43 g of potassium carbonate was added, thereto was addeda solution of 0.24 mL of 2-aminomethyl-1,3-dioxolan in 3 mL ofacetonitrile under cooling with ice, and the mixture was stirred for 2hours under cooling with ice. Thereto was further added 80 μL of2-aminomethyl-1,3-dioxolan, and the mixture was stirred for 2 hoursunder cooling with ice. Water and ethyl acetate were added thereto undercooling with ice, the organic layer was separated, washed with asaturated aqueous sodium chloride solution and dried over anhydroussodium sulfate, and the solvent was distilled off under reducedpressure. The resultant residue was purified by basic silica gel columnchromatography using an eluent of hexane:ethyl acetate=20:1 to obtain0.44 g of 6-chloro-N-(1,3-dioxolan-2-ylmethyl)-3-nitropyridin-2-amine asa yellow solid.

¹H-NMR (CDCl₃) δ: 3.90-4.00 (2H, m), 4.00-4.12 (2H, m), 5.16 (1H, t,J=3.3 Hz), 6.63 (1H, d, J=8.7 Hz), 8.35 (1H, d, J=8.7 Hz), 8.40-8.60(1H, broad)

REFERENCE EXAMPLE 51

To a suspension of 13 g of iron powder in 650 mL of ethanol and 350 mLof water, 14 g of sodium chloride was added, and the mixture was heatedunder reflux while stirring for 20 minutes. Thereto was added 10 g of6-chloro-N-(1,3-dioxolan-2-ylmethyl)-3-nitropyridin-2-amine at 65° C.,and the mixture was heated under reflux while stirring for 30 minutes.The insoluble substance was filtered off, the solvent was distilled offto be 300 mL under reduced pressure, ethyl acetate was added thereto,the organic layer was separated, and the aqueous layer was extractedwith ethyl acetate. The organic layer and the extract were combined, theresultant solution was dried over anhydrous sodium sulfate, and thesolvent was distilled off under reduced pressure. The resultant residuewas purified by basic silica gel column chromatography using an eluentof ethyl acetate to obtain 6.5 g of3-amino-6-chloro-2-(1,3-dioxolan-2-ylmethyl)aminopyridine as a lightpurple solid.

¹H-NMR (CDCl₃) δ: 3.15 (2H, s), 3.68 (2H, dd, J=6.0, 4.2 Hz), 3.88-3.98(2H, m), 3.98-4.06 (2H, m), 4.50-4.60 (1H, m), 5.14 (1H, t, J=4.2 Hz),6.51 (1H, d, J=7.7 Hz), 6.80 (1H, d, J=7.7 Hz)

REFERENCE EXAMPLE 52

By the same technique as in Reference Example 16,6-chloro-4-(1,3-dioxolan-2-ylmethyl)pyrido(2,3-b)pyrazin-3(4H)-one wasobtained from 3-amino-6-chloro-2-(1,3-dioxolan-2-ylmethyl)aminopyridineand ethyl oxoacetate.

¹H-NMR (CDCl₃) δ: 3.87-3.96 (2H, m), 4.08-4.18 (2H, m), 4.56 (2H, d,J=5.4 Hz), 5.58 (1H, t, J=5.4 Hz), 7.30 (1H, d, J=8.3 Hz), 8.10 (1H, d,J=8.3 Hz), 8.32 (1H, s)

REFERENCE EXAMPLE 53

To a solution of 0.10 g of6-chloro-4-(1,3-dioxolan-2-ylmethyl)pyrido(2,3-b)pyrazin-3(4H)-one in 3mL of N,N-dimethylformamide, 0.57 g of cesium fluoride was added, andthe mixture was stirred at 90 to 100° C. for 1 hour 10 minutes. Theretowas further added 0.57 g of cesium fluoride, and the mixture was stirredat 90 to 100° C. for 1 hour 30 minutes. Thereto were added ethyl acetateand water, the organic layer was separated, and the aqueous layer wasextracted with ethyl acetate. The organic layer and the extract werecombined, the resultant solution was washed sequentially with dilutedhydrochloric acid and a saturated aqueous sodium chloride solution, anddried over anhydrous magnesium sulfate, and the solvent was distilledoff under reduced pressure. The resultant residue was purified by silicagel column chromatography using an eluent of chloroform:methanol=50:1 toobtain 60 mg of4-(1,3-dioxolan-2-ylmethyl)-6-fluoropyrido(2,3-b)pyrazin-3(4H)-one as alight yellow solid.

¹H-NMR (CDCl₃) δ: 3.86-3.96 (2H, m), 4.06-4.16 (2H, m), 4.53 (2H, d,J=5.4 Hz), 5.54 (1H, t, J=5.4 Hz), 6.91 (1H, dd, J=8.4, 2.4 Hz), 8.25(1H, dd, J=8.4, 7.3 Hz), 8.30 (1H, s)

REFERENCE EXAMPLE 54

By the same technique as in Reference Example 4,(6-fluoro-3-oxopyrido(2,3-b)pyrazin-4(3H)-yl)acetaldehyde was obtainedfrom 4-(1,3-dioxolan-2-ylmethyl)-6-fluoropyrido(2,3-b)pyrazin-3(4H)-one.

¹H-NMR (CDCl₃) δ: 5.27 (2H, s), 6.93 (1H, dd, J=8.5, 2.4 Hz), 8.30 (1H,dd, J=8.5, 7.1 Hz), 8.34 (1H, s), 9.75 (1H, s)

REFERENCE EXAMPLE 55

By the same technique as in Reference Example 4,(6-chloro-3-oxopyrido(2,3-b)pyrazin-4(3H)-yl)acetaldehyde was obtainedfrom 6-chloro-4-(1,3-dioxolan-2-ylmethyl)pyrido(2,3-b)pyrazin-3(4H)-one.

¹H-NMR (CDCl₃) δ: 5.31 (2H, s), 7.32 (1H, d, J=8.3 Hz), 8.15 (1H, d,J=8.3 Hz), 8.36 (1H, s), 9.76 (1H, s)

REFERENCE EXAMPLE 56

To a solution of 0.30 g of6-chloro-4-(1,3-dioxolan-2-ylmethyl)pyrido(2,3-b)pyrazin-3(4H)-one and78 mg of 1,2,4-triazole in 9 mL of N,N-dimethylformamide, 48 mg of 60%sodium hydride was added, and the mixture was stirred at 40 to 50° C.for 1 hour 30 minutes. Thereto was further added 78 mg of 1,2,4-triazoleand 48 mg of 60% sodium hydride, and the mixture was stirred at 40 to50° C. for 1 hour 30 minutes, and stirred at 60 to 70° C. for 20minutes. The reaction mixture was charged with a mixed solution of ethylacetate and water and neutralized with 2.0 mol/L hydrochloric acid, andthe insoluble substance was filtered off. The organic layer wasseparated and the aqueous layer was extracted with ethyl acetate. Theorganic layer and the extract were combined, the resultant solution waswashed sequentially with water and a saturated aqueous sodium chloridesolution and dried over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure. The resultant residue was purifiedby flash silica gel column chromatography using gradient elution withhexane:ethyl acetate=80:20 to 30:70 and washed with diisopropyl ether toobtain 77 mg of4-(1,3-dioxolan-2-ylmethyl)-6-(1H-1,2,4-triazole-1-yl)pyrido(2,3-b)pyrazin-3(4H)-oneas a light red solid.

¹H-NMR (CDCl₃) δ: 3.86-3.96 (2H, m), 4.04-4.14 (2H, m), 4.67 (2H, d,J=4.9 Hz), 5.47 (1H, t, J=4.9 Hz), 7.93 (1H, d, J=8.5 Hz), 8.16 (1H, s),8.34-8.37 (2H, m), 9.19 (1H, s)

REFERENCE EXAMPLE 57

To a solution of 1.0 g of monoethyl oxalate in 14 mL of dichloromethane,0.47 g of 5,6,7,8-tetrahydroquinoxaline, 91 μL of concentrated sulfuricacid, 1.7 g of sodium persulfate, and a suspension of 60 mg of silvernitrate in 14 mL of water were added, and the mixture was heated underreflux while stirring for 1 hour 30 minutes. To the reaction mixture,1.7 g of sodium persulfate and 60 mg of silver nitrate were furtheradded, and the mixture was heated under reflux for 1 hour 50 minutes.The reaction mixture was charged with chloroform and adjusted to pH 7.5with a saturated aqueous sodium hydrogen carbonate solution, theinsoluble substance was filtered off, and the organic layer wasseparated. The organic layer was washed with a saturated aqueous sodiumchloride solution, and dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure. The resultant residuewas purified by flash silica gel column chromatography using gradientelution with hexane:ethyl acetate=90:10 to 67:33 to obtain 0.16 g ofethyl 5,6,7,8-tetrahydroquinoxaline-2-carboxylate as a yellow oilysubstance.

¹H-NMR (CDCl₃) δ: 1.44 (3H, t, J=7.1 Hz), 1.92-2.00 (4H, m), 3.00-3.10(4H, m), 4.50 (2H, q, J=7.1 Hz), 9.02 (1H, s)

REFERENCE EXAMPLE 58

To a solution of 0.16 g of ethyl5,6,7,8-tetrahydroquinoxaline-2-carboxylate in 1.5 mL oftetrahydrofuran, 29 mg of lithium aluminum hydride was added undercooling with ice, the mixture was stirred for 45 minutes, 29 mg oflithium aluminum hydride was further added thereto, and the mixture wasstirred for 30 minutes. Thereto were added ethyl acetate and water, theinsoluble substance was filtered off, sodium chloride was added to afiltrate, the organic layer was separated, and the aqueous layer wasextracted with ethyl acetate. The organic layer and the extract werecombined, the resultant solution was washed with a saturated aqueoussodium chloride solution, and dried over anhydrous magnesium sulfate,and the solvent was distilled off under reduced pressure to obtain 0.10g of (5,6,7,8-tetrahydroquinoxalin-2-yl)methanol as a brown solid.

¹H-NMR (CDCl₃) δ: 1.89-1.98 (4H, m), 2.92-3.01 (4H, m), 4.76 (2H, s),8.33 (1H, s)

REFERENCE EXAMPLE 59

By the same technique as in Reference Example 67,5,6,7,8-tetrahydroquinoxaline-2-carbaldehyde was obtained from(5,6,7,8-tetrahydroquinoxalin-2-yl)methanol.

¹H-NMR (CDCl₃) δ: 1.96-2.01 (4H, m), 3.03-3.10 (4H, m), 8.91 (1H, s),10.09 (1H, s)

REFERENCE EXAMPLE 60

To a suspension of 1.0 g of 1-(trifluoroacetyl)piperidin-4-aminehydrochloride in 20 mL of dichloromethane, 0.71 g of2,3-dihydro-1,4-benzodioxine-6-carbaldehyde and 0.25 mL of acetic acidwere added, and the mixture was stirred at room temperature for 2 hours.To the reaction mixture, 1.37 g of sodium triacetoxyborohydride wasadded, and the mixture was stirred at the same temperature for 30minutes. The solvent was distilled off under reduced pressure, water andethyl acetate were then added thereto, and the mixture was adjusted topH 1.5 with 1 mol/L hydrochloric acid. The aqueous layer was separatedand washed with ethyl acetate, thereto was added ethyl acetate, and theaqueous layer was adjusted to pH 7.8 with a saturated aqueous sodiumhydrogen carbonate solution. The organic layer was separated, and theaqueous layer was extracted with ethyl acetate. The organic layer andthe extract were combined, the resultant solution was washed with asaturated aqueous sodium chloride solution and dried over anhydrousmagnesium sulfate, and the solvent was distilled off under reducedpressure to obtain 1.4 g ofN-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-1-(trifluoroacetyl)piperidin-4-amineas a colorless oily substance.

¹H-NMR (CDCl₃) δ: 1.35-1.50 (2H, m), 1.90-2.00 (2H, m), 2.80-2.88 (1H,m), 3.02-3.12 (1H, m), 3.18-3.28 (1H, m), 3.71 (2H, s), 3.90-4.00 (1H,m), 4.25 (4H, s), 4.25-4.32 (1H, m), 6.75-6.83 (3H, m)

REFERENCE EXAMPLE 61

To a solution of 1.4 g ofN-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-1-(trifluoroacetyl)piperidin-4-aminein 20 mL of dichloromethane, 0.88 g of di-tert-butyl dicarbonate wasadded, and the mixture was stirred at room temperature for 30 minutes.Thereto was added 0.28 mL of triethylamine, the mixture was stirred atthe same temperature for 10 minutes, and then 0.44 g of di-tert-butyldicarbonate was added and the mixture was stirred for 10 minutes. Afterstirring at 40° C. for 30 minutes, the solvent was distilled off underreduced pressure, and the resultant residue was purified by silica gelcolumn chromatography using an eluent of hexane:ethyl acetate=1:1 toobtain 1.4 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(trifluoroacetyl)piperidin-4-yl) carbamate as a white foam.

¹H-NMR (CDCl₃) δ: 1.44 (9H, s), 1.60-1.82 (4H, m), 2.60-2.80 (1H, m),3.00-3.20 (1H, m), 3.95-4.05 (1H, m), 4.15-4.40 (3H, m), 4.25 (4H, s),4.50-4.65 (1H, m), 6.60-6.75 (2H, m), 6.70-6.73 (1H, m), 6.79 (1H, d,J=8.3 Hz)

REFERENCE EXAMPLE 62

To a solution of 1.4 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(trifluoroacetyl)piperidin-4-yl)carbamate in 20 mL of methanol, 5 mLof water and 0.53 g of potassium carbonate were added, and the mixturewas stirred at room temperature for 1 hour 15 minutes. The solvent wasdistilled off under reduced pressure, and ethyl acetate and water wereadded thereto. The organic layer was separated, and the aqueous layerwas extracted with ethyl acetate. The organic layer and the extract werecombined, the resultant solution was washed sequentially with water anda saturated aqueous sodium chloride solution and dried over anhydrousmagnesium sulfate, and the solvent was distilled off under reducedpressure to obtain 1.0 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl) carbamate as alight yellow oily substance.

¹H-NMR (CDCl₃) δ: 1.42 (9H, s), 1.35-1.70 (4H, m), 2.55-2.70 (2H, m),3.05-3.15 (2H, m), 4.15-4.35 (3H, m), 4.24 (4H, s), 6.66-6.71 (1H, m),6.73-6.75 (1H, m), 6.78 (1H, d, J=8.3 Hz)

REFERENCE EXAMPLE 63

By the same technique as in Reference Example 60,N-(2,3-dihydro-1,4-dioxino(2,3-c)pyridin-7-ylmethyl)-1-(trifluoroacetyl)piperidin-4-aminewas obtained from 1-(trifluoroacetyl)piperidin-4-amine hydrochloride and2,3-dihydro-1,4-dioxino(2,3-c)pyridine-7-carbaldehyde.

¹H-NMR (CDCl₃) δ: 1.39-1.51 (2H, m), 1.93-2.01 (2H, m), 2.79-2.88 (1H,m), 3.02-3.10 (1H, m), 3.19-3.27 (1H, m), 3.80 (2H, s), 3.90-3.99 (1H,m), 4.25-4.35 (5H, m), 6.80 (1H, s), 8.11 (1H, s)

REFERENCE EXAMPLE 64

By the same technique as in Reference Example 61, tert-butyl(2,3-dihydro-1,4-dioxino(2,3-c)pyridin-7-ylmethyl)(1-(trifluoroacetyl)piperidin-4-yl)carbamate was obtained fromN-(2,3-dihydro-1,4-dioxino(2,3-c)pyridin-7-ylmethyl)-1-(trifluoroacetyl)piperidin-4-amine.

¹H-NMR (CDCl₃) δ: 1.43 (9H, s), 1.37-1.84 (4H, m), 2.60-2.80 (1H, m),3.00-3.20 (1H, m), 3.98-4.06 (1H, m), 4.25-4.41 (7H, m), 4.54-4.62 (1H,m), 6.74 (1H, s), 8.05 (1H, s)

REFERENCE EXAMPLE 65

By the same technique as in Reference Example 62, tert-butyl(2,3-dihydro-1,4-dioxino(2,3-c)pyridin-7-ylmethyl)(piperidin-4-yl)carbamatewas obtained from tert-butyl(2,3-dihydro-1,4-dioxino(2,3-c)pyridin-7-ylmethyl)(1-(trifluoroacetyl)piperidin-4-yl)carbamate.

¹H-NMR (CDCl₃) δ: 1.39 (9H, s), 1.34-1.71 (4H, m), 2.52-2.70 (2H, m),3.04-3.11 (2H, m), 4.11-4.48 (7H, m), 6.75 (1H, s), 8.05 (1H, s)

REFERENCE EXAMPLE 66

To a solution of 0.11 kg of5-hydroxy-2-(hydroxymethyl)-1,4-dihydropyridin-4-one disodium salt in600 mL of dimethyl sulfoxide, 0.25 kg of potassium carbonate and 81 mLof 1-bromo-3-chloropropane were added, and the mixture was stirred at 80to 90° C. for 3 hours 20 minutes, at 90 to 100° C. for 45 minutes, andfurther at 80 to 95° C. for 5 hours. The reaction mixture was cooled toroom temperature, water and chloroform were then added thereto, and theinsoluble substance was filtered off. The organic layer was separatedand the aqueous layer was extracted with chloroform. The organic layerand the extract were combined, the resultant solution was dried overanhydrous magnesium sulfate, and the solvent was distilled off underreduced pressure. The resultant residue was purified by silica gelcolumn chromatography using an eluent of chloroform:methanol=10:1 toobtain 31 g of(3,4-dihydro-2H-(1,4)dioxepino(2,3-c)pyridin-8-yl)methanol as a brownoily substance.

¹H-NMR (CDCl₃) δ: 2.23-2.30 (2H, m), 4.24-4.28 (2H, m), 4.33-4.37 (2H,m), 4.63 (2H, s), 6.82 (1H, s), 8.19 (1H, s)

REFERENCE EXAMPLE 67

To a solution of 13 g of(3,4-dihydro-2H-(1,4)dioxepino(2,3-c)pyridin-8-yl)methanol in 250 mL ofchloroform, 13 g of manganese dioxide was added, and the mixture wasstirred at room temperature for 30 minutes. Thereto was further added 20g of manganese dioxide dividedly, the mixture was then stirred at roomtemperature for 20 minutes and at 60 to 70° C. for 1 hour 30 minutes.The reaction mixture was cooled to room temperature, the insolublesubstance was then filtered off, and the solvent was distilled off underreduced pressure. The resultant residue was purified by silica gelcolumn chromatography using an eluent of hexane:ethyl acetate=1:1 toobtain 2.2 g of3,4-dihydro-2H-(1,4)dioxepino(2,3-c)pyridine-8-carbaldehyde as a lightyellowish white solid.

¹H-NMR (CDCl₃) δ: 2.28-2.35 (2H, m), 4.36-4.43 (4H, m), 7.53 (1H, s),8.36 (1H, s), 9.94 (1H, s)

REFERENCE EXAMPLE 68

By the same technique as in Reference Example 60,N-(3,4-dihydro-2H-(1,4)dioxepino(2,3-c)pyridin-8-ylmethyl)-1-(trifluoroacetyl)piperidin-4-aminewas obtained from 1-(trifluoroacetyl)piperidin-4-amine hydrochloride and3,4-dihydro-2H-(1,4)dioxepino(2,3-c)pyridine-8-carbaldehyde.

¹H-NMR (CDCl₃) δ: 1.39-1.52 (2H, m), 1.93-2.01 (2H, m), 2.12-2.30 (2H,m), 2.80-2.88 (1H, m), 3.01-3.11 (1H, m), 3.18-3.28 (1H, m), 3.81 (2H,s), 3.90-3.99 (1H, m), 4.21-4.38 (5H, m), 6.85 (1H, s), 8.18 (1H, s)

REFERENCE EXAMPLE 69

By the same technique as in Reference Example 61, tert-butyl(3,4-dihydro-2H-(1,4)dioxepino(2,3-c)pyridin-8-ylmethyl)(1-(trifluoroacetyl)piperidin-4-yl)carbamate was obtained fromN-(3,4-dihydro-2H-(1,4)dioxepino(2,3-c)pyridin-8-ylmethyl)-1-(trifluoroacetyl)piperidin-4-amine.

¹H-NMR (CDCl) δ: 1.41 (9H, s), 1.55-1.90 (4H, m), 2.20-2.30 (2H, m),2.65-2.80 (1H, m), 3.04-3.21 (1H, m), 3.70-4.50 (8H, m), 4.55-4.64 (1H,m), 6.78 (1H, s), 8.13 (1H, s)

REFERENCE EXAMPLE 70

By the same technique as in Reference Example 62, tert-butyl(3,4-dihydro-2H-(1,4)dioxepino(2,3-c)pyridin-8-ylmethyl)(piperidin-4-yl)carbamatewas obtained from tert-butyl(3,4-dihydro-2H-(1,4)dioxepino(2,3-c)pyridin-8-ylmethyl)(1-(trifluoroacetyl)piperidin-4-yl)carbamate.

¹H-NMR (CDCl₃) δ: 1.40-1.72 (13H, m), 2.17-2.28 (2H, m), 2.50-2.70 (2H,m), 3.01-3.11 (2H, m), 4.10-4.50 (7H, m), 6.79 (1H, s), 8.13 (1H, s)

REFERENCE EXAMPLE 71

By the same technique as in Reference Example 1, ethyl(2E)-3-(3-amino-5-chloropyridin-2-yl)acrylate and ethyl(2E)-3-(6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)acrylate were obtainedfrom 2,5-dichloropyridin-3-amine and ethyl acrylate.

Ethyl (2E)-3-(3-amino-5-chloropyridin-2-yl)acrylate

¹H-NMR (CDCl₃) δ: 1.33 (3H, t, J=7.1 Hz), 4.04 (2H, s), 4.27 (2H, q,J=7.1 Hz), 6.91 (1H, d, J=15.2 Hz), 7.01 (1H, d, J=2.0 Hz), 7.71 (1H, d,J=15.2 Hz), 8.00 (1H, d, J=2.0 Hz)

Ethyl (2E)-3-(6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)acrylate

¹H-NMR (DMSO-d₆) δ: 1.28 (3H, t, J=7.1 Hz), 4.22 (2H, q, J=7.1 Hz), 6.77(1H, d, J=16.0 Hz), 6.78 (1H, d, J=9.5 Hz), 7.75 (1H, d, J=16.0 Hz),7.80-7.84 (1H, m), 7.94 (1H, d, J=9.5 Hz), 8.82-8.87 (1H, m), 11.98 (1H,s)

REFERENCE EXAMPLE 72

By the same technique as in Reference Example 3, ethyl(2E)-3-(5-(1,3-dioxolan-2-ylmethyl)-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)acrylatewas obtained from ethyl(2E)-3-(6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)acrylate and2-bromomethyl-1,3-dioxolan.

¹H-NMR (CDCl₃) δ: 1.38 (3H, t, J=7.1 Hz), 3.84-3.93 (2H, m), 3.96-4.06(2H, m), 4.32 (2H, q, J=7.1 Hz), 4.53 (2H, d, J=4.1 Hz), 5.20 (1H, t,J=4.1 Hz), 6.63 (1H, d, J=16.1 Hz), 6.96 (1H, d, J=9.8 Hz), 7.77 (1H, d,J=16.1 Hz), 7.91 (1H, d, J=9.8 Hz), 8.03-8.06 (1H, m), 8.68 (1H, d,J=1.7 Hz)

REFERENCE EXAMPLE 73

By the same technique as in Reference Example 4, ethyl(2E)-3-(6-oxo-5-(2-oxoethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)acrylatewas obtained from ethyl(2E)-3-(5-(1,3-dioxolan-2-ylmethyl)-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)acrylate.

¹H-NMR (CDCl₃) δ: 1.36 (3H, t, J=7.2 Hz), 4.30 (2H, q, J=7.2 Hz), 5.19(2H, s), 6.59 (1H, d, J=16.1 Hz), 7.00 (1H, d, J=9.8 Hz), 7.34-7.38 (1H,m), 7.71 (1H, d, J=16.1 Hz), 7.99 (1H, d, J=9.8 Hz), 8.72 (1H, d, J=1.5Hz), 9.79 (1H, s)

REFERENCE EXAMPLE 74

By the same technique as in Reference Example 2,7-chloro-1,5-naphthyridin-2(1H)-one was obtained from ethyl(2E)-3-(3-amino-5-chloropyridin-2-yl)acrylate.

¹H-NMR (DMSO-d₆) δ: 6.77 (1H, d, J=9.8 Hz), 7.70-7.73 (1H, m), 7.94 (1H,d, J=9.8 Hz), 8.49 (1H, d, J=2.2 Hz), 11.95-12.05 (1H, broad)

REFERENCE EXAMPLE 75

By the same technique as in Reference Example 3,7-chloro-1-(1,3-dioxolan-2-ylmethyl)-1,5-naphthyridin-2(1H)-one wasobtained from 7-chloro-1,5-naphthyridin-2(1H)-one and2-bromomethyl-1,3-dioxolan.

¹H-NMR (CDCl₃) δ: 3.84-4.06 (4H, m), 4.46 (2H, d, J=4.2 Hz), 5.20 (1H,t, J=4.2 Hz), 6.92 (1H, d, J=9.8 Hz), 7.89 (1H, d, J=9.8 Hz), 7.96 (1H,d, J=2.0 Hz), 8.46 (1H, d, J=2.0 Hz)

REFERENCE EXAMPLE 76

By the same technique as in Reference Example 4,(7-chloro-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde was obtained from7-chloro-1-(1,3-dioxolan-2-ylmethyl)-1,5-naphthyridin-2(1H)-one.

¹H-NMR (CDCl₃) δ: 5.13 (2H, s), 6.96 (1H, d, J=9.9 Hz), 7.31-7.33 (1H,m), 7.96 (1H, d, J=9.9 Hz), 8.51 (1H, d, J=2.0 Hz), 9.78 (1H, s)

REFERENCE EXAMPLE 77

To a solution 0.16 g of(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde in 2 mL ofdichloromethane, 0.14 g of tert-butyl (piperidin-4-yl) carbamate, 41 μLof acetic acid and 0.23 g of sodium triacetoxyborohydride were added,and the mixture was stirred at room temperature for 1 hour 30 minutes.The reaction mixture was charged with chloroform and a saturated aqueoussodium hydrogen carbonate solution and adjusted to pH 8.5, the organiclayer was separated, and the aqueous layer was extracted withchloroform. The organic layer and the extract were combined, theresultant solution was washed sequentially with water and a saturatedaqueous sodium chloride solution and dried over anhydrous magnesiumsulfate, and the solvent was distilled off under reduced pressure. Theresultant residue was purified by basic silica gel column chromatographyusing an eluent of chloroform:methanol=19:1 to obtain 0.23 g oftert-butyl(1-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamateas a yellow oily substance.

¹H-NMR (CDCl₃) δ: 1.36-1.48 (2H, m), 1.45 (9H, s), 1.91-1.99 (2H, m),2.22-2.31 (2H, m), 2.61-2.68 (2H, m), 2.90-2.97 (2H, m), 3.42-3.54 (1H,m), 3.98 (3H, s), 4.32-4.47 (3H, m), 6.74 (1H, d, J=9.8 Hz), 7.18 (1H,d, J=2.3 Hz), 7.84 (1H, d, J=9.8 Hz), 8.28 (1H, d, J=2.3 Hz)

REFERENCE EXAMPLE 78

To a solution of 0.23 g of tert-butyl(1-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamatein 5 mL of ethanol, 5 mL of a 6.0 mol/L hydrogen chloride/ethanolsolution was added at room temperature and the mixture was stirred for 1hour. The solvent was distilled off under reduced pressure, diethylether was added to the resultant residue, and the solid was filtered offto obtain 0.22 g of1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-onehydrochloride as a light yellow solid.

¹H-NMR (D₂O) δ: 1.93-2.07 (2H, m), 2.34-2.44 (2H, m), 3.20-3.33 (2H, m),3.57-3.67 (3H, m), 3.90-4.01 (2H, m), 4.05 (3H, s), 4.73-4.85 (2H, m),6.89 (1H, d, J=9.8 Hz), 7.50 (1H, d, J=2.3 Hz), 8.06 (1H, d, J=9.8 Hz),8.42 (1H, d, J=2.3 Hz)

REFERENCE EXAMPLE 79

To a solution of 0.15 g of 1,8-naphthyridin-2(1H)-one in 2 mL ofN,N-dimethylformamide, 45 mg of 60% sodium hydride was added, and themixture was stirred at 50 to 65° C. for 1 hour. Thereto was added asolution of 0.44 g of 1-tert-butyl 4-ethyl4-(3-((methylsulfonyl)oxy)propyl)piperidine-1,4-dicarboxylate in 1.2 mLof N,N-dimethylformamide, and the reaction mixture was stirred at 80 to90° C. for 1 hour 30 minutes and cooled to room temperature, and waterand ethyl acetate were then added thereto. The organic layer wasseparated, and the aqueous layer was extracted with ethyl acetate. Theorganic layer and the extract were combined, the resultant solution waswashed with a saturated aqueous sodium chloride solution and dried overanhydrous magnesium sulfate, and the solvent was distilled off underreduced pressure. The resultant residue was purified by silica gelcolumn chromatography using an eluent of hexane:ethyl acetate=3:2 toobtain 0.29 g of 1-tert-butyl 4-ethyl4-(3-(2-oxo-1,8-naphthyridin-1(2H)-yl)propyl)piperidine-1,4-dicarboxylateas a colorless oily substance.

¹H-NMR (CDCl₃) δ: 1.22 (3H, t, J=7.1 Hz), 1.32-1.41 (2H, m), 1.44 (9H,s), 1.65-1.72 (4H, m), 2.05-2.11 (2H, m), 2.80-3.00 (2H, m), 3.75-4.00(2H, m), 4.13 (2H, q, J=7.1 Hz), 4.43-4.48 (2H, m), 6.72 (1H, d, J=9.5Hz), 7.18 (1H, dd, J=7.7, 4.7 Hz), 7.65 (1H, d, J=9.5 Hz), 7.88 (1H, dd,J=7.7, 1.8 Hz), 8.57 (1H, dd, J=4.7, 1.8 Hz)

REFERENCE EXAMPLE 80

To a solution of 0.53 g of 1-tert-butyl 4-ethyl4-(3-(2-oxo-1,8-naphthyridin-1(2H)-yl)propyl)piperidine-1,4-dicarboxylatein 6 mL of chloroform, 25 mL of trifluoroacetic acid was added, and themixture was stirred at room temperature for 2 hours. The solvent wasdistilled off under reduced pressure, a saturated aqueous sodiumhydrogen carbonate solution was added to the resultant residue and themixture was neutralized, and chloroform was then added thereto. Theorganic layer was separated, and the aqueous layer was extracted withchloroform. The organic layer and the extract were combined, theresultant solution was washed with a saturated aqueous sodium chloridesolution and dried over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure to obtain 0.47 g of ethyl4-(3-(2-oxo-1,8-naphthyridin-1(2H)-yl)propyl)piperidine-4-carboxylate asa colorless oily substance.

¹H-NMR (CDCl₃) δ: 1.22 (3H, t, J=7.1 Hz), 1.45-1.54 (2H, m), 1.64-1.71(4H, m), 2.12-2.20 (2H, m), 2.67-2.78 (2H, m), 3.02-3.08 (2H, m), 4.14(2H, q, J=7.1 Hz), 4.41-4.47 (3H, m), 6.73 (1H, d, J=9.5 Hz), 7.17 (1H,dd, J=7.6, 4.7 Hz), 7.64 (1H, d, J=9.5 Hz), 7.87 (1H, dd, J=7.6, 1.7Hz), 8.57 (1H, dd, J=4.7, 1.7 Hz)

REFERENCE EXAMPLE 81

By the same technique as in Reference Example 79, 1-tert-butyl 4-ethyl4-(3-(2-oxo-1,7-naphthyridin-1(2H)-yl)propyl)piperidine-1,4-dicarboxylatewas obtained from 1,7-naphthyridin-2(1H)-one and 1-tert-butyl 4-ethyl4-(3-((methanesulfonyl)oxy)propyl)piperidine-1,4-dicarboxylate.

¹H-NMR (CDCl₃) δ: 1.20-1.74 (9H, m), 1.44 (9H, s), 2.05-2.13 (2H, m),2.74-2.95 (2H, m), 3.77-3.95 (2H, m), 4.14 (2H, q, J=7.1 Hz), 4.26-4.31(2H, m), 6.89 (1H, d, J=9.5 Hz), 7.43 (1H, d, J=5.1 Hz), 7.65 (1H, d,J=9.5 Hz), 8.45 (1H, d, J=5.1 Hz), 8.74 (1H, s)

REFERENCE EXAMPLE 82

To a solution of 0.50 g of 1-tert-butyl 4-ethyl4-(3-(2-oxo-1,7-naphthyridin-1(2H)-yl)propyl)piperidine-1,4-dicarboxylatein 3 mL of ethanol, 3.0 mL of a 4.0 mol/L hydrogen chloride/ethylacetate solution was added, and the mixture was stirred at roomtemperature for 1 hour. Thereto was added 2.0 mL of a 4.0 mol/L hydrogenchloride/ethyl acetate solution, and the mixture was stirred at roomtemperature for 1 hour. The solid was filtered off to obtain 0.29 g ofethyl4-(3-(2-oxo-1,7-naphthyridin-1(2H)-yl)propyl)piperidine-4-carboxylatehydrochloride as a light yellow solid.

¹H-NMR (DMSO-d₆) δ: 1.11 (3H, t, J=7.1 Hz), 1.48-1.58 (2H, m), 1.62-1.72(4H, m), 2.03-2.11 (2H, m), 2.70-2.82 (2H, m), 3.14-3.25 (2H, m), 4.07(2H, q, J=7.1 Hz), 4.24-4.30 (2H, m), 7.03 (1H, d, J=9.5 Hz), 8.02 (1H,d, J=5.4 Hz), 8.09 (1H, d, J=9.5 Hz), 8.54 (1H, d, J=5.4 Hz), 8.88-9.07(2H, m), 9.17 (1H, s)

REFERENCE EXAMPLE 83

To a solution of 1.2 mL of diisopropylamine in 20 mL of tetrahydrofuran,5.8 mL of a 1.6 mol/L butyryl lithium/hexane solution was dropped at−78° C., and the mixture was stirred at the same temperature for 1 hour.Thereto was dropped a solution of 2.0 g of 1-tert-butyl 4-ethylpiperidine-1,4-dicarboxylate in 2 mL of tetrahydrofuran, and the mixturewas stirred for 1 hour. Thereto was added 1.7 mL of benzyl 3-bromopropylether, and the temperature of the reaction mixture was increased to roomtemperature and the mixture was stirred for 10 hours. The mixture wascharged with water and adjusted to pH 2.0 with 6 mol/L hydrochloricacid. The organic layer was separated, and the aqueous layer wasextracted with ethyl acetate. The organic layer and the extract werecombined, the resultant solution was washed with a saturated aqueoussodium chloride solution, and dried over anhydrous magnesium sulfate,and the solvent was distilled off under reduced pressure. The resultantresidue was purified by silica gel column chromatography using an eluentof hexane:ethyl acetate=10:1 to obtain 2.0 g of 1-tert-butyl 4-ethyl4-(3-(benzyloxy)propyl)piperidine-1,4-dicarboxylate as a colorless oilysubstance.

¹H-NMR (CDCl₃) δ: 1.25 (3H, t, J=7.2 Hz), 1.25-1.45 (2H, m), 1.45 (9H,s), 1.50-1.65 (4H, m), 2.05-2.15 (2H, m), 2.75-3.00 (2H, m), 3.42 (2H,t, J=6.1 Hz), 3.75-3.95 (2H, m), 4.16 (2H, q, J=7.2 Hz), 4.47 (2H, s),7.26-7.37 (5H, m)

REFERENCE EXAMPLE 84

To a solution of 2.0 g of 1-tert-butyl 4-ethyl4-(3-(benzyloxy)propyl)piperidine-1,4-dicarboxylate in 20 mL of ethanol,a suspension of 0.30 g of 10% palladium carbon in 2 mL of ethanol wasadded, and the mixture was stirred for 4 hours under a hydrogenatmosphere. The insoluble substance was filtered off, and the solventwas distilled off under reduced pressure to obtain 1.7 g of 1-tert-butyl4-ethyl 4-(3-hydroxypropyl)piperidine-1,4-dicarboxylate as a colorlessoily substance.

¹H-NMR (CDCl₃) δ: 1.27 (3H, t, J=7.2 Hz), 1.23-1.62 (6H, m), 1.45 (9H,s), 2.05-2.15 (2H, m), 2.80-2.95 (2H, m), 3.58-3.63 (2H, m), 3.75-3.95(2H, m), 4.18 (2H, q, J=7.2 Hz)

REFERENCE EXAMPLE 85

To a solution of 1.7 g of 1-tert-butyl 4-ethyl4-(3-hydroxypropyl)piperidine-1,4-dicarboxylate in 20 mL oftetrahydrofuran, 0.82 mL of triethylamine and 0.58 mL of methanesulfonylchloride were added at 5° C., and the mixture was stirred at roomtemperature for 1 hour. Thereto were added ethyl acetate and water. Theorganic layer was separated and the aqueous layer was extracted withethyl acetate. The organic layer and the extract were combined, theresultant solution was washed with a saturated aqueous sodium chloridesolution and dried over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure to obtain 1.9 g of 1-tert-butyl4-ethyl 4-(3-((methanesulfonyl)oxy)propyl)piperidine-1,4-dicarboxylateas a colorless oily substance.

¹H-NMR (CDCl₃) δ: 1.25-1.75 (6H, m), 1.28 (3H, t, J=7.2 Hz), 1.45 (9H,s), 2.05-2.15 (2H, m), 2.80-2.95 (2H, m), 3.00 (3H, s), 3.80-3.95 (2H,m), 4.19 (2H, q, J=7.2 Hz), 4.15-4.22 (2H, m)

REFERENCE EXAMPLE 86

To 184 mL of 80% trifluoroacetic acid, 4.60 g of1-(1,3-dioxolan-2-ylmethyl)-7-methoxy-1,5-naphthyridin-2(1H)-one wasdissolved, and the resultant solution was stirred at room temperaturefor 11 hours and at 60° C. for 3.5 hours. The reaction mixture wascharged with chloroform and alkalified with a 10% aqueous sodiumhydroxide solution under cooling with ice. The organic layer wasseparated, and washed with an aqueous sodium chloride solution and driedover anhydrous magnesium sulfate, and the solvent was distilled offunder reduced pressure to obtain(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde as a yellowsolid.

To 58 mL of chloroform, the obtained(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde was dissolved,2.67 g of tert-butyl (piperidin-4-yl)carbamate and 0.80 g of acetic acidwere added, and the mixture was stirred at room temperature for 1.5hours. To the reaction mixture, 4.23 g of sodium triacetoxyborohydridewas added, and the mixture was stirred for 15 hours. Thereto was added asaturated aqueous sodium hydrogen carbonate solution, and the organiclayer was separated. The organic layer was washed with a saturatedaqueous sodium chloride solution and dried over anhydrous magnesiumsulfate, and the solvent was distilled off under reduced pressure. Theresultant residue was purified by silica gel column chromatography usingsilica gel; Silica Gel 60N made by KANTO CHEMICAL CO., INC. and aneluent of chloroform:methanol=10:1 to obtain 4.36 g of tert-butyl(1-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamateas a white solid.

¹H-NMR (CDCl₃) δ: 1.38-1.44 (2H, m), 1.45 (9H, s), 1.90-2.00 (2H, m),2.21-2.30 (2H, m), 2.59-2.70 (2H, m), 2.87-2.99 (2H, m), 3.43-3.54 (1H,m), 3.98 (3H, s), 4.29-4.38 (2H, m), 4.40-4.49 (1H, m), 6.74 (1H, d,J=9.6 Hz), 7.16-7.19 (1H, m), 7.84 (1H, d, J=9.6 Hz), 8.28 (1H, d, J=2.3Hz)

REFERENCE EXAMPLE 87

To a solution of 4.36 g of tert-butyl(1-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamatein 50 mL of chloroform, 10 mL of trifluoroacetic acid was added, and themixture was stirred at room temperature for 1 hour. After the solventwas distilled off under reduced pressure, the reaction mixture wasalkalified with a saturated aqueous sodium hydrogen carbonate solution,the solvent was then distilled off under reduced pressure, and theresultant residue was purified by silica gel column chromatography usingsilica gel; Chromatorex-NH made by Fuji Silysia Chemical Ltd., and aneluent of chloroform:methanol=10:1 to obtain 2.16 g of1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-oneas a yellow oily substance.

¹H-NMR (CDCl₃) δ: 1.39 (4H, m), 1.81-1.86 (2H, m), 2.17-2.24 (2H, m),2.63-2.73 (3H, m), 2.95-3.00 (2H, m), 3.98 (3H, s), 4.34-4.39 (2H, m),6.75 (1H, d, J=9.6 Hz), 7.23 (1H, d, J=2.3 Hz), 7.84 (1H, d, J=9.6 Hz),8.28 (1H, d, J=2.3 Hz)

REFERENCE EXAMPLE 88

To 50 mL of chloroform, 5.00 g of 3-bromo-1,5-naphthyridin wasdissolved, 6.40 g of m-chloroperbenzoic acid was added thereto, and themixture was stirred at room temperature for 1.5 hours. To the reactionmixture, a 5% aqueous sodium thiosulfate solution and chloroform wereadded, and the organic layer was separated, washed sequentially with a5% aqueous sodium hydroxide solution and a saturated aqueous sodiumchloride solution and dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure. The resultant residuewas purified by silica gel column chromatography using silica gel;Chromatorex-NH made by Fuji Silysia Chemical Ltd., and an eluent ofethyl acetate:hexane=1:1 to obtain 1.95 g of3-bromo-1,5-naphthyridin-5-oxide as a light yellow solid.

¹H-NMR (CDCl₃) δ: 7.55 (1H, dd, J=8.7, 6.0 Hz), 7.99 (1H, d, J=8.7 Hz),8.55 (1H, d, J=6.0 Hz), 9.04 (1H, d, J=2.3 Hz), 9.23 (1H, d, J=2.3 Hz)

REFERENCE EXAMPLE 89

To a solution of 0.50 g of 3-bromo-1,5-naphthyridin-5-oxide in 10 mL ofchloroform, 0.51 g of p-toluenesulfonyl chloride, 1.04 g of potassiumcarbonate and 3 mL of water were added, and the mixture was stirred atroom temperature overnight. Thereto were added water and chloroform, andthe solid was filtered off to obtain 0.39 g of7-bromo-1,5-naphthyridin-2(1H)-one as a white solid.

¹H-NMR (DMSO-d₆) δ: 6.77 (1H, d, J=9.6 Hz), 7.85-7.87 (1H, m), 7.90 (1H,d, J=9.6 Hz), 8.53 (1H, d, J=1.8 Hz), 11.69-12.50 (1H, m)

REFERENCE EXAMPLE 90

To 5 mL of N,N-dimethylformamide, 770 mg of7-bromo-1,5-naphthyridin-2(1H)-one was dissolved, 278 mg of 60% sodiumhydride was added, and the mixture was stirred at room temperature for 1hour. Thereto was added 1.1 mL of 2-bromomethyl-1,3-dioxolan at 110° C.for 4 days. The reaction mixture was cooled to room temperature, andthen ethyl acetate and 1 mol/L hydrochloric acid were added. The organiclayer was separated, washed sequentially with water and a saturatedaqueous sodium chloride solution and dried over anhydrous magnesiumsulfate, and the solvent was distilled off under reduced pressure. Theresultant residue was purified by silica gel column chromatography usingsilica gel; Silica Gel 60 made by KANTO CHEMICAL CO., INC., and aneluent of ethyl acetate:hexane 2:1 to obtain 467 mg of7-bromo-1-(1,3-dioxolan-2-ylmethyl)-1,5-naphthyridin-2(1H)-one as alight yellow solid.

¹H-NMR (CDCl₃) δ: 3.87-3.91 (2H, m), 4.00-4.03 (2H, m), 4.46 (2H, d,J=4.1 Hz), 5.20 (1H, t, J=4.1 Hz), 6.94 (1H, d, J=9.6 Hz), 7.86-7.89(1H, m), 8.11 (1H, d, J=1.8 Hz), 8.56 (1H, d, J=1.8 Hz)

REFERENCE EXAMPLE 91

To 10 mL of 1-methyl-2-pyrrolidinone, 358 mg of7-bromo-1-(1,3-dioxolan-2-ylmethyl)-1,5-naphthyridin-2(1H)-one and 183mg of copper cyanide were suspended, and the suspension was heated underreflux for 70 minutes. The reaction mixture was cooled to roomtemperature, ethyl acetate was then added thereto, the mixture waswashed sequentially with water and a saturated saline water and driedover anhydrous magnesium sulfate, and the solvent was distilled offunder reduced pressure. The resultant residue was purified by silica gelcolumn chromatography using silica gel; Silica Gel 60 made by KANTOCHEMICAL CO., INC., and an eluent of ethyl acetate:hexane 1:1 to obtain145 mg of 7-cyano-1-(1,3-dioxolan-2-ylmethyl)-1,5-naphthyridin-2(1H)-oneas a yellow solid.

¹H-NMR (CDCl₃) δ: 3.87-3.90 (2H, m), 3.98-4.02 (2H, m), 4.49 (2H, d,J=4.1 Hz), 5.17 (1H, t, J=4.1 Hz), 7.06 (1H, d, J=9.6 Hz), 7.95 (1H, d,J=9.6 Hz), 8.23-8.24 (1H, m), 8.72 (1H, d, J=1.8 Hz)

REFERENCE EXAMPLE 92

To 5 mL of 90% trifluoroacetic acid, 215 mg of7-cyano-1-(1,3-dioxolan-2-ylmethyl)-1,5-naphthyridin-2(1H)-one wasdissolved, and the resultant solution was stirred at 60° C. for 7 hours.After the reaction mixture was cooled to room temperature and alkalifiedwith a 10% aqueous sodium hydroxide solution, the solvent was thendistilled off under reduced pressure. The resultant residue was purifiedby silica gel column chromatography using silica gel; Silica Gel 60 madeby KANTO CHEMICAL CO., INC., and an eluent of ethyl acetate:hexane=1:1,and washed with water to obtain 90 mg of(7-cyano-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde as a light yellowsolid.

¹H-NMR (CDCl₃) δ: 5.19 (2H, s), 7.09-7.11 (1H, m), 7.52-7.53 (1H, m),8.02 (1H, d, J=9.6 Hz), 8.76 (1H, d, J=1.4 Hz), 9.83 (1H, s)

REFERENCE EXAMPLE 93

To a solution of 83 mg of(7-cyano-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde and 80 mg oftert-butyl piperidin-4-yl-carbamate in 10 mL of chloroform, 24 μL ofacetic acid was added, and the mixture was stirred at room temperaturefor 1.5 hours. To the reaction mixture, 136 mg of sodiumtriacetoxyborohydride was added, and the mixture was stirred for 1.5hours. A saturated aqueous sodium hydrogen carbonate solution was addedto the reaction mixture, and the solvent was distilled off under reducedpressure. The resultant residue was purified by silica gel columnchromatography using silica gel; Chromatorex-NH made by Fuji SilysiaChemical Ltd., and an eluent of ethyl acetate:hexane=1:1 to obtain 76 mgof tert-butyl(1-(2-(7-cyano-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamateas a brown solid.

¹H-NMR (CDCl₃) δ: 1.33-1.39 (2H, m), 1.44 (9H, s), 1.92-1.97 (2H, m),2.22-2.28 (2H, m), 2.64-2.68 (2H, m), 2.85-2.90 (2H, m), 3.46-3.51 (1H,m), 4.30-4.35 (2H, m), 4.41-4.45 (1H, m), 7.05 (1H, d, J=9.6 Hz), 7.94(1H, d, J=9.6 Hz), 8.12-8.15 (1H, m), 8.72 (1H, d, J=1.4 Hz)

REFERENCE EXAMPLE 94

To a solution of 3.15 g of 3-chloro-6-methoxypyrazin-2-amine in 20 mL oftriethylamine, 2.6 mL of ethyl acrylate and 0.50 g ofbis(tri-tert-butylphosphine)palladium(0) were added, and the mixture wasstirred at an external temperature of 120 to 130° C. for 2 hours in asealed tube. Thereto was further added 5 mL of triethylamine, and themixture was stirred at the same temperature for 4 hours 50 minutes. Thereaction mixture was cooled to room temperature and left overnight, then0.5 mL of ethyl acrylate and 0.25 g ofbis(tri-tert-butylphosphine)palladium(0) were added thereto and themixture was stirred at an external temperature of 115 to 125° C. for 9hours 20 minutes in a sealed tube. The reaction mixture was cooled toroom temperature, water and ethyl acetate were then added thereto, theorganic layer was separated and the aqueous layer was extracted withethyl acetate. The organic layer and the extract were combined, theresultant solution was washed with a saturated aqueous sodium chloridesolution and dried over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure. The resultant residue was purifiedby silica gel column chromatography using an eluent of hexane:ethylacetate=4:1 to obtain 2.55 g of ethyl(2E)-3-(3-amino-5-methoxypyrazin-2-yl)acrylate as a yellow solid.

¹H-NMR (CDCl₃) δ: 1.32 (3H, t, J=7.1 Hz), 3.91 (3H, s), 4.26 (2H, q,J=7.1 Hz), 4.72 (2H, s), 6.73 (1H, d, J=15.1 Hz), 7.61-7.68 (2H, m)

REFERENCE EXAMPLE 95

To a solution of 0.85 g of ethyl(2E)-3-(3-amino-5-methoxypyrazin-2-yl)acrylate in 40 mL of ethanol, 2.20g of a 28% sodium methoxide/methanol solution was added, and the mixturewas heated under reflux while stirring for 7 hours 30 minutes. Thereaction mixture was cooled to room temperature, the solvent was thendistilled off under reduced pressure, and to the resultant residue,water, a saturated aqueous ammonium chloride solution and chloroformwere added, the organic layer was separated, and the aqueous layer wasadded with sodium chloride and extracted with chloroform. The organiclayer and the extract were combined, the resultant solution was washedwith a saturated aqueous sodium chloride solution and dried overanhydrous magnesium sulfate, and the solvent was distilled off underreduced pressure. Diethyl ether was added to the resultant residue, andthe solid was filtered off and washed with diethyl ether to obtain 0.64g of 3-methoxypyrido(2,3-b)pyrazin-6(5H)-one as a light yellow solid.

¹H-NMR (CDCl₃) δ: 4.06 (3H, s), 6.72 (1H, d, J=9.8 Hz), 7.92 (1H, d,J=9.8 Hz), 8.13 (1H, s), 9.68 (1H, s)

REFERENCE EXAMPLE 96

To a solution of 0.30 g of 3-methoxypyrido(2,3-b)pyrazin-6(5H)-one in 6mL of N,N-dimethylformamide, 0.35 g of potassium carbonate was added,and the mixture was stirred at 65 to 75° C. for 10 minutes. Thereto wasadded 0.21 mL of 2-bromomethyl-1,3-dioxolan, and the mixture was stirredat 95 to 100° C. for 1 hour 30 minutes. Thereto were further added 0.05mL of 2-bromomethyl-1,3-dioxolan and 120 mg of potassium carbonate, andthe mixture was stirred at 95 to 100° C. for 2 hours 15 minutes. Thereaction mixture was cooled to room temperature, and water and ethylacetate were then added thereto, the organic layer was separated, andthe aqueous layer was extracted with ethyl acetate. The organic layerand the extract were combined, and the resultant solution was washedwith a saturated aqueous sodium chloride solution and dried overanhydrous magnesium sulfate, and the solvent was distilled off underreduced pressure. The resultant residue was purified by silica gelcolumn chromatography using an eluent of hexane:ethyl acetate=2:1 toobtain 0.13 g of5-(1,3-dioxolan-2-ylmethyl)-3-methoxypyrido(2,3-b)pyrazin-6(5H)-one as ayellow solid.

¹H-NMR (CDCl₃) δ: 3.88-3.92 (2H, m), 4.06-4.12 (5H, m), 4.63 (2H, d,J=5.1 Hz), 5.51 (1H, t, J=5.1 Hz), 6.78 (1H, d, J=9.8 Hz), 7.85 (1H, d,J=9.8 Hz), 8.12 (1H, s)

REFERENCE EXAMPLE 97

To 0.12 g of5-(1,3-dioxolan-2-ylmethyl)-3-methoxypyrido(2,3-b)pyrazin-6(5H)-one, 5mL of a 90% aqueous trifluoroacetic acid solution was added, and themixture was stirred at room temperature for 3 hours 30 minutes. Asaturated aqueous sodium hydrogen carbonate solution and chloroform wereadded to the reaction mixture, the organic layer was separated and theaqueous layer was extracted with chloroform. The organic layer and theextract were combined, the resultant solution was washed with asaturated aqueous sodium chloride solution and dried over anhydrousmagnesium sulfate, and the solvent was distilled off under reducedpressure to obtain 0.12 g of(3-methoxy-6-oxopyrido(2,3-b)pyrazin-5(6H)-yl)acetaldehyde as a lightyellow solid.

¹H-NMR (CDCl₃) δ: 3.99 (3H, s), 5.24 (2H, s), 6.82 (1H, d, J=9.8 Hz),7.94 (1H, d, J=9.8 Hz), 8.15 (1H, s), 9.71 (1H, s)

REFERENCE EXAMPLE 98

By the same technique as in Reference Example 60,1-(4-benzylmorpholin-2-yl)-N-(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)methanaminewas obtained from 1-(4-benzylmorpholin-2-yl)methanamine and2,3-dihydro(1,4)dioxino(2,3-c)pyridine-7-carbaldehyde.

By the same technique as in Reference Example 61, tert-butyl((4-benzylmorpholin-2-yl)methyl)(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)carbamatewas obtained from1-(4-benzylmorpholin-2-yl)-N-(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)methanamine.

¹H-NMR (CDCl₃) δ: 1.34-1.49 (9H, m), 1.81-1.93 (1H, m), 2.09-2.18 (1H,m), 2.56-2.66 (1H, m), 2.70-2.77 (1H, m), 3.20-3.85 (7H, m), 4.23-4.35(4H, m), 4.37-4.64 (2H, m), 6.68-6.74 (1H, m), 7.20-7.36 (5H, m), 8.07(1H, s)

REFERENCE EXAMPLE 99

By the same technique as in Reference Example 25, tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(morpholin-2-ylmethyl)carbamatewas obtained from tert-butyl((4-benzylmorpholin-2-yl)methyl)(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)carbamate.

¹H-NMR (CDCl₃) δ: 1.35-1.57 (9H, m), 2.75-3.10 (2H, m), 3.25-3.56 (4H,m), 3.93-4.19 (3H, m), 4.25-4.44 (4H, m), 4.46-4.67 (2H, m), 6.70-6.92(1H, m), 8.10-8.19 (1H, m), 9.80-10.4 (1H, broad)

REFERENCE EXAMPLE 100

To a solution of 0.62 g of2,6-dichloro-3-fluoro-5-((methoxymethoxy)methyl)pyridine in 18 mL ofN,N-dimethylformamide, 0.54 mL of triethylamine, 0.15 mL of formic acidand 0.15 g of tetrakis(triphenylphosphine)palladium(0) were added, andthe mixture was stirred at 90 to 100° C. for 4 hours 30 minutes under anitrogen atmosphere. Thereto were added water and ethyl acetate, theinsoluble substance was filtered off, the organic layer was separated,and the aqueous layer was extracted with ethyl acetate. The organiclayer and the extract were combined, the resultant solution was washedsequentially with water and a saturated aqueous sodium chloride solutionand dried over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure. The resultant residue was purifiedby silica gel column chromatography using an eluent of hexane:ethylacetate=8:1 to obtain 0.39 g of2-chloro-5-fluoro-3-((methoxymethoxy)methyl)pyridine as a colorless oilysubstance.

¹H-NMR (CDCl₃) δ: 3.43 (3H, s), 4.65 (2H, d, J=0.8 Hz), 4.80 (2H, s),7.66 (1H, dd, J=8.4, 3.0 Hz), 8.18 (1H, d, J=3.0 Hz)

REFERENCE EXAMPLE 101

To a solution of 0.10 g of2-chloro-5-fluoro-3-((methoxymethoxy)methyl)pyridine in 3 mL of dioxane,0.20 g of potassium carbonate, 68 μL of trimethylboroxin and 56 mg oftetrakis(triphenylphosphine)palladium(0) were added, and the mixture washeated under reflux while stirring for 2 hours under a nitrogenatmosphere. Thereto were added 0.20 g of potassium carbonate, 68 μL oftrimethylboroxin and 56 mg of tetrakis(triphenylphosphine)palladium(0),and the mixture was heated under reflux while stirring for 2 hours undera nitrogen atmosphere. Thereto were added 0.20 g of potassium carbonate,68 μL of trimethylboroxin and 56 mg oftetrakis(triphenylphosphine)palladium(0), and the mixture was heatedunder reflux while stirring for 1 hour under a nitrogen atmosphere. Theinsoluble substance was filtered off, and the solvent was distilled offunder reduced pressure. The resultant residue was purified by silica gelcolumn chromatography using an eluent of chloroform:methanol=100:1 toobtain 93 mg of a colorless oily substance. The substance was purifiedby basic silica gel column chromatography using an eluent of chloroformto obtain 64 mg of 5-fluoro-3-((methoxymethoxy)methyl)-2-methylpyridineas a colorless oily substance.

¹H-NMR (CDCl₃) δ: 2.49 (3H, s), 3.42 (3H, s), 4.58 (2H, s), 4.76 (2H,s), 7.47 (1H, dd, J=9.2, 2.7 Hz), 8.27 (1H, d, J=2.7 Hz)

REFERENCE EXAMPLE 102

To a solution of 0.49 g of5-fluoro-3-((methoxymethoxy)methyl)-2-methylpyridine in 20 mL ofdioxane, 10 mL of 6.0 mol/L hydrochloric acid was added, and the mixturewas stirred at 30 to 40° C. for 1 hour. Thereto were added water andethyl acetate, and the mixture was adjusted to pH 5.5 with a 20% aqueoussodium hydroxide solution and a saturated aqueous sodium hydrogencarbonate solution. The organic layer was separated, and the aqueouslayer was extracted with ethyl acetate twice. The organic layer and theextract were combined, the resultant solution was washed with water anda saturated aqueous sodium chloride solution and dried over anhydrousmagnesium sulfate, and the solvent was distilled off under reducedpressure to obtain 0.41 g of (5-fluoro-2-methylpyridin-3-yl)methanol asa light yellow oily substance.

¹H-NMR (CDCl₃) δ: 2.40 (1H, t, J=5.2 Hz), 2.46 (3H, s), 4.72 (2H, d,J=5.2 Hz), 7.53 (1H, dd, J=9.1, 2.6 Hz), 8.24 (1H, d, J=2.6 Hz)

REFERENCE EXAMPLE 103

To a solution of 32 mg of (5-fluoro-2-methylpyridin-3-yl)methanol in 2mL of dichloromethane, 80 mg of molecular sieves 3 A and 40 mg of4-methylmorpholine N-oxide were added, and the mixture was stirred atroom temperature for 30 minutes. Thereto was added 6.0 mg of tetrapropylammonium perruthenate, and the mixture was stirred at room temperaturefor 1 hour 30 minutes. The insoluble substance was filtered off, and thesolvent was distilled off under reduced pressure. The resultant residuewas purified by silica gel column chromatography using an eluent ofchloroform:methanol=100:1 to obtain 20 mg of5-fluoro-2-methylnicotinaldehyde as a colorless oily substance.

¹H-NMR (CDCl₃) δ: 2.87 (3H, d, J=1.0 Hz), 7.81 (1H, dd, J=8.0, 3.0 Hz),8.56 (1H, d, J=3.0 Hz), 10.33 (1H, d, J=2.2 Hz)

REFERENCE EXAMPLE 104

To a suspension of 77 mg of sodium hydride in 2 mL ofN,N-dimethylformamide, 0.13 g of imidazole was added, and the mixturewas stirred at room temperature for 10 minutes. To the reaction mixture,0.20 g of7-bromo-1-((1,3-dioxolan-2-yl)methyl)-1,5-naphthyridin-2(1H)-one wasadded dividedly, and then 18 mg of copper (II) oxide was added thereto.The reaction mixture was stirred at 135 to 140° C. for 30 minutes. Thereaction mixture was cooled to room temperature, then chloroform andwater were added thereto, the organic layer was separated, and theaqueous layer was extracted with chloroform. The organic layer and theextract were combined, the resultant solution was dried over anhydrousmagnesium sulfate, and the solvent was distilled off under reducedpressure. To the resultant residue, a mixed solvent of diethyl ether:ethyl:acetate (3:1) was added, and the solid was filtered off to obtain0.12 g of1-((1,3-dioxolan-2-yl)methyl)-7-(1H-imidazol-1-yl)-1,5-naphthyridin-2(1H)-oneas a yellow solid.

¹H-NMR (CDCl₃) δ: 3.86-4.20 (4H, m), 4.55 (2H, d, J=4.0 Hz), 5.18 (1H,t, J=4.0 Hz), 6.97 (1H, d, J=9.9 Hz), 7.32 (1H, s), 7.40 (1H, s), 7.95(1H, d, J=9.9 Hz), 7.98 (1H, s), 8.01 (1H, d, J=2.1 Hz), 8.65 (1H, d,J=2.1 Hz)

REFERENCE EXAMPLE 105

To 0.12 g of1-((1,3-dioxolan-2-yl)methyl)-7-(1H-imidazol-1-yl)-1,5-naphthyridin-2(1H)-one,2 mL of an 80% aqueous trifluoroacetic acid solution was added at roomtemperature, and the mixture was stirred at 50 to 60° C. for 1 hour 30minutes. The reaction mixture was cooled to room temperature, and thesolvent was then distilled off under reduced pressure. The resultantresidue was charged with chloroform and water and adjusted to pH 7.8with a 20% aqueous sodium hydroxide solution. The organic layer wasseparated and the aqueous layer was extracted with chloroform, and thenfurther extracted with ethyl acetate. The organic layer and the extractwere combined, the resultant solution was dried over anhydrous magnesiumsulfate, and the solvent was distilled off under reduced pressure toobtain 0.12 g of(7-(1H-imidazol-1-yl)-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde as ayellow solid.

¹H-NMR (DMSO-d₆) δ: 5.35 (2H, s), 6.92 (1H, d, J=9.8 Hz), 7.20 (1H, s),7.22 (1H, s), 8.00 (1H, s), 8.05 (1H, d, J=9.8 Hz), 8.12 (1H, d, J=2.2Hz), 8.96 (1H, d, J=2.2 Hz), 9.70 (1H, s)

REFERENCE EXAMPLE 106

By the same technique as in Reference Example 60, benzyl(3R,4R)-4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)-3-hydroxypiperidine-1-carboxylatewas obtained from benzyl(3R,4R)-4-amino-3-hydroxypiperidine-1-carboxylate and2,3-dihydro(1,4)dioxino(2,3-c)pyridine-7-carbaldehyde.

By the same technique as in Reference Example 61, benzyl(3R,4R)-4-((tert-butoxycarbonyl)(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)-3-hydroxypiperidine-1-carboxylatewas obtained from benzyl(3R,4R)-4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)-3-hydroxypiperidine-1-carboxylate.

By the same technique as in Reference Example 25, tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)((3R,4R)-3-hydroxypiperidin-4-yl)carbamatewas obtained from benzyl(3R,4R)-4-((tert-butoxycarbonyl)(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)-3-hydroxypiperidine-1-carboxylate.

¹H-NMR (CDCl₃) δ: 1.28-1.57 (9H, m), 1.90-2.40 (2H, m), 2.70-3.10 (2H,m), 3.43-3.80 (2H, m), 4.00-4.35 (2H, m), 4.40-4.86 (6H, m), 7.20-7.40(1H, m), 8.23-8.39 (1H, m), 9.10-9.90 (2H, m)

REFERENCE EXAMPLE 107

By the same technique as in Reference Example 42, tert-butyl(1-(2-(3-methoxy-6-oxopyrido(2,3-b)pyrazin-5(6H)-yl)ethyl)piperidin-4-yl)carbamatewas obtained from(3-methoxy-6-oxopyrido(2,3-b)pyrazin-5(6H)-yl)acetaldehyde andtert-butyl piperidin-4-ylcarbamate.

¹H-NMR (CDCl₃) δ: 1.30-1.50 (11H, m), 1.87-1.96 (2H, m), 2.18-2.30 (2H,m), 2.66-2.74 (2H, m), 2.94-3.06 (2H, m), 3.39-3.52 (1H, m), 4.06 (3H,s), 4.34-4.46 (1H, m), 4.53-4.61 (2H, m), 6.76 (1H, d, J=9.6 Hz), 7.84(1H, d, J=9.6 Hz), 8.11 (1H, s)

REFERENCE EXAMPLE 108

By the same technique as in Reference Example 65,5-(2-(4-aminopiperidin-1-yl)ethyl)-3-methoxypyrido(2,3-b)pyrazin-6(5H)-onehydrochloride was obtained from tert-butyl(1-(2-(3-methoxy-6-oxopyrido(2,3-b)pyrazin-5(6H)-yl)ethyl)piperidin-4-yl)carbamate.

¹H-NMR (DMSO-d₆) δ: 1.88-2.20 (4H, m), 3.05-3.19 (2H, m), 3.20-3.68 (3H,m), 3.71-3.82 (2H, m), 4.11 (3H, s), 4.68-4.78 (2H, m), 6.77 (1H, d,J=9.6 Hz), 8.01 (1H, d, J=9.6 Hz), 8.29 (1H, s), 8.30-8.38 (3H, broad),10.58-10.70 (1H, broad)

REFERENCE EXAMPLE 109

To 2.9 g of 5-chloro-2-methoxypyrimidin-4-amine, 2.35 mL of ethylacrylate, 18 mL of triethylamine, and 0.46 g ofbis(tri-tert-butylphosphine)palladium(0) were added, and the mixture wasstirred at an external temperature of 115 to 130° C. for 5 hours in asealed tube. Thereto were further added 5 mL of triethylamine, 0.30 g ofbis(tri-tert-butylphosphine)palladium(0) and 0.5 mL of ethyl acrylate,and the mixture was stirred at an external temperature of 120 to 130° C.for 6 hours 30 minutes in a sealed tube. The reaction mixture was cooledto room temperature, and water and ethyl acetate were added thereto. Theorganic layer was separated, and the aqueous layer was extracted withchloroform and ethyl acetate. The organic layer and the extract werecombined, the resultant solution was dried over anhydrous magnesiumsulfate, and the solvent was distilled off under reduced pressure. Theresultant residue was purified by silica gel column chromatography usingan eluent of hexane:ethyl acetate=1:1 to obtain 0.89 g of ethyl(2E)-3-(4-amino-2-methoxypyrimidin-5-yl)acrylate as a yellow solid.

¹H-NMR (CDCl₃) δ: 1.33 (3H, t, J=7.1 Hz), 3.95 (3H, s), 4.26 (2H, q,J=7.1 Hz), 5.45 (2H, s), 6.28 (1H, d, J=16.1 Hz), 7.57 (1H, d, J=16.1Hz), 8.29 (1H, s)

REFERENCE EXAMPLE 110

To a solution of 0.87 g of ethyl(2E)-3-(4-amino-2-methoxypyrimidin-5-yl)acrylate in 50 mL of methanol,2.31 g of a 28% sodium methoxide/methanol solution was added at roomtemperature, and the mixture was heated under reflux while stirring for4 hours. The reaction mixture was cooled to room temperature, and thesolvent was then distilled off under reduced pressure. To the resultantresidue, a saturated aqueous ammonium chloride solution and chloroformwere added, the organic layer was separated, and the aqueous layer wasextracted with chloroform. The organic layer and the extract werecombined, the resultant solution was dried over anhydrous magnesiumsulfate, and the solvent was distilled off under reduced pressure. Thesolid thus obtained was washed with diethyl ether to obtain 0.55 g of2-methoxypyrido(2,3-d)pyrimidin-7(8H)-one as a yellow solid.

¹H-NMR (CDCl₃) δ: 4.07 (3H, s), 6.56 (1H, d, J=9.5 Hz), 7.68 (1H, d,J=9.5 Hz), 8.68 (1H, s), 9.32 (1H, s)

REFERENCE EXAMPLE 111

To a suspension of 0.50 g of 2-methoxypyrido(2,3-d)pyrimidin-7(8H)-onein 7.5 mL of N,N-dimethylformamide, 0.59 g of potassium carbonate wasadded at room temperature, the temperature was increased to 60 to 80°C., and the mixture was stirred for 1 hour. Thereto was added 0.35 mL of2-bromomethyl-1,3-dioxolan at 80° C., the temperature of the reactionmixture was increased to 103° C., and the mixture was stirred for 3hours 30 minutes. The reaction mixture was cooled to room temperature,and water and chloroform were added thereto. The organic layer wasseparated, and the aqueous layer was extracted with chloroform. Theorganic layer and the extract were combined, the resultant solution waswashed with a saturated aqueous sodium chloride solution and dried overanhydrous magnesium sulfate, and the solvent was distilled off underreduced pressure. The resultant residue was purified by silica gelcolumn chromatography using an eluent of chloroform:methanol=75:1 toobtain 0.60 g of8-(1,3-dioxolan-2-ylmethyl)-2-methoxypyrido(2,3-d)pyrimidin-7(8H)-one asa yellow solid.

¹H-NMR (CDCl₃) δ: 3.87-3.95 (2H, m), 4.05-4.13 (2H, m), 4.09 (3H, s),4.59 (2H, d, J=5.1 Hz), 5.52 (1H, d, J=5.1 Hz), 6.60 (1H, d, J=9.5 Hz),7.62 (1H, d, J=9.5 Hz), 8.65 (1H, s)

REFERENCE EXAMPLE 112

To 0.20 g of8-(1,3-dioxolan-2-ylmethyl)-2-methoxypyrido(2,3-d)pyrimidin-7(8H)-one, 5mL of an 80% aqueous trifluoroacetic acid solution was added, and themixture was stirred at room temperature for 8 hours. To the reactionmixture, a saturated aqueous sodium hydrogen carbonate solution andchloroform were added. The organic layer was separated, and the aqueouslayer was extracted with chloroform. The organic layer and the extractwere combined, the resultant solution was washed with a saturatedaqueous sodium chloride solution and dried over anhydrous magnesiumsulfate, and the solvent was distilled off under reduced pressure toobtain 0.21 g of(2-methoxy-7-oxopyrido(2,3-d)pyrimidin-8(7H)-yl)acetaldehyde as a yellowoily substance.

¹H-NMR (CDCl₃) δ: 4.04 (3H, s), 5.25 (2H, s), 6.64 (1H, d, J=9.5 Hz),7.72 (1H, d, J=9.5 Hz), 8.71 (1H, s), 9.72 (1H, s)

REFERENCE EXAMPLE 113

To a solution of 0.65 g of tert-butyl3-(aminomethyl)piperidine-1-carboxylate in 5 mL of dichloromethane, 0.50g of (2,3-dihydro(1,4)dioxino(2,3-c)pyridine-7-carbaldehyde and 0.17 mLof acetic acid were added. Subsequently, 0.96 g of sodiumtriacetoxyborohydride was added thereto and the mixture was stirred atroom temperature for 1 hour 15 minutes. The reaction mixture was chargedwith chloroform and adjusted to pH 8.6 with a saturated aqueous sodiumhydrogen carbonate solution and a 20% aqueous sodium hydroxide solution,the organic layer was separated, and the aqueous layer was extractedwith chloroform. The organic layer and the extract were combined, theresultant solution was washed with water and a saturated aqueous sodiumchloride solution and dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure to obtain 1.3 g oftert-butyl3-(((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)methyl)piperidine-1-carboxylateas a yellow oily substance.

¹H-NMR (CDCl₃) δ: 1.12-1.92 (5H, m), 1.45 (9H, s), 2.20-2.72 (3H, m),2.80-2.90 (1H, m), 3.78 (2H, s), 3.78-3.98 (2H, m), 4.22-4.35 (4H, m),6.84 (1H, s), 8.10 (1H, s)

REFERENCE EXAMPLE 114

To a solution of 1.3 g of tert-butyl3-(((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)methyl)piperidine-1-carboxylatein 10 mL of methanol, 0.54 mL of ethyl trifluoroacetate was added, and amixture was stirred at room temperature for 2 hours, and then stirred at40 to 45° C. for 3 hours. Thereto was added 0.54 mL of ethyltrifluoroacetate, and the mixture was heated under reflux while stirringfor 3 hours. The mixture was cooled to room temperature, and the solventwas then distilled off under reduced pressure. The resultant residue waspurified by silica gel column chromatography using an eluent ofhexane:ethyl acetate=1:1 to obtain 0.47 g of tert-butyl3-(((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(trifluoroacetyl)amino)-methyl)piperidine-1-carboxylateas a colorless oily substance.

¹H-NMR (CDCl₃) δ: 1.07-2.10 (5H, m), 1.44 (9H, s), 2.58-2.66 (1H, m),2.70-2.79 (1H, m), 3.20-3.50 (2H, m), 3.80-4.00 (2H, m), 4.26-4.36 (4H,m), 4.58-4.68 (2H, m), 6.66 (1H, s), 8.11 (1H, s)

REFERENCE EXAMPLE 115

To a solution of 0.43 g of tert-butyl3-(((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(trifluoroacetyl)amino)methyl)piperidine-1-carboxylatein 3 mL of chloroform, 3 mL of trifluoroacetic acid was added, and themixture was stirred at room temperature for 1 hour 40 minutes. Thesolvent was distilled off under reduced pressure. The resultant residuewas charged with chloroform and water, and adjusted to pH 8.0 with anaqueous sodium hydrogen carbonate solution and a 20% aqueous sodiumhydroxide solution. The organic layer was separated, and the aqueouslayer was extracted with chloroform. The organic layer and the extractwere combined, the resultant solution was washed with water and asaturated aqueous sodium chloride solution and dried over anhydrousmagnesium sulfate, and the solvent was distilled off under reducedpressure to obtain 0.15 g ofN-(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)-2,2,2-trifluoro-N-(piperidin-3-ylmethyl)acetamideas a light yellow oily substance.

¹H-NMR (CDCl₃) δ: 1.08-1.26 (1H, m), 1.48-1.62 (1H, m), 1.68-2.15 (3H,m), 2.32-2.47 (1H, m), 2.54-2.66 (1H, m), 3.00-3.12 (2H, m), 3.22-3.30(1H, m), 3.32-3.44 (1H, m), 4.24-4.36 (4H, m), 4.61 (2H, s), 6.67 (1H,s), 8.11 (1H, s)

REFERENCE EXAMPLE 116

To a solution of 1.5 g of methyl 2,6-dichloro-5-fluoronicotinate in 12mL of methanol, a solution of 1.3 g of 28% sodium methoxide/methanol in3 mL of methanol was dropped, and the mixture was stirred at roomtemperature for 40 minutes. Thereto were added water and ethyl acetate,the organic layer was separated, and the aqueous layer was extractedwith ethyl acetate. The organic layer and the extract were combined, theresultant solution was washed with water and a saturated aqueous sodiumchloride solution and dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure to obtain 1.2 g ofmethyl 2-chloro-5-fluoro-6-methoxynicotinate as a white solid.

¹H-NMR (CDCl₃) δ: 3.92 (3H, s), 4.09 (3H, s), 7.92 (1H, d, J=9.8 Hz)

REFERENCE EXAMPLE 117

To a solution of 1.5 g of methyl 2-chloro-5-fluoro-6-methoxynicotinatein 15 mL of N,N-dimethylformamide, 0.38 g oftetrakis(triphenylphosphine)palladium(0), 1.4 mL of triethylamine, and0.38 mL of formic acid were added at room temperature, and the mixturewas stirred at 50 to 60° C. for 1 hour under a nitrogen atmosphere, andthen stirred at 90 to 100° C. for 2 hours 20 minutes. Thereto werefurther added 1.4 mL of triethylamine, 0.38 g oftetrakis(triphenylphosphine)palladium(0) and 0.38 mL of formic acid atroom temperature, and the mixture was stirred at 90 to 100° C. for 1hour. After cooling to room temperature, the reaction mixture wascharged with ethyl acetate and water, and adjusted to pH 4.8 with 2mol/L hydrochloric acid. The organic layer was separated, and theaqueous layer was extracted with ethyl acetate. The organic layer andthe extract were combined, and the resultant solution was washed with asaturated aqueous sodium chloride solution. A mixed solvent ofchloroform:methanol was added to the organic layer to dissolve theinsoluble substance, and dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure. Ethyl acetate wasadded to the resultant residue, and the solid was filtered off to obtain0.30 g of methyl 5-fluoro-6-methoxynicotinate as a yellow solid.

¹H-NMR (CDCl₃) δ: 3.92 (3H, s), 4.09 (3H, s), 7.88 (1H, dd, J=10.5, 2.0Hz), 8.61 (1H, d, J=2.0 Hz)

REFERENCE EXAMPLE 118

To a suspension of 0.24 g of lithium aluminum hydride in 6 mL oftetrahydrofuran, a solution of 0.58 g of methyl5-fluoro-6-methoxynicotinate in 3.5 mL of tetrahydrofuran was droppedunder cooling with ice. After warming to room temperature, the mixturewas stirred for 30 minutes. Thereto was dropped a saturated aqueoussodium hydrogen carbonate solution under cooling with ice, afterstirring for 10 minutes, the reaction mixture was filtered throughcelite, and the filtration residue was washed with ethyl acetate andwater. The organic layer of the filtrate was separated, and the aqueouslayer was extracted with ethyl acetate. The organic layer and theextract were combined, the resultant solution was washed with water anda saturated aqueous sodium chloride solution and dried over anhydrousmagnesium sulfate, and the solvent was distilled off under reducedpressure to obtain 0.55 g of (5-fluoro-6-methoxypyridin-3-yl)methanol asa brown oily substance.

¹H-NMR (CDCl₃) δ: 1.72 (1H, t, J=5.7 Hz), 4.03 (3H, s), 4.65 (2H, d,J=5.7 Hz), 7.40 (1H, dd, J=10.7, 2.0 Hz), 7.89 (1H, d, J=2.0 Hz)

REFERENCE EXAMPLE 119

To a solution of 0.54 g of (5-fluoro-6-methoxypyridin-3-yl)methanol in 5mL of dichloromethane, 1.5 g of manganese dioxide was added. The mixturewas stirred at room temperature for 3 hours, thereto were then added0.89 g of manganese dioxide and 4 mL of dichloromethane, and the mixturewas stirred for 1 hour. Thereto were further added 1.5 g of manganesedioxide and 2 mL of dichloromethane, and the mixture was stirred at roomtemperature for 2 hours 30 minutes. After leaving overnight, theinsoluble substance was filtered off, and the filtration residue waswashed with chloroform. The solvent was distilled off under reducedpressure to obtain 0.48 g of 5-fluoro-6-methoxynicotinaldehyde as ayellow solid.

¹H-NMR (CDCl₃) δ: 4.13 (3H, s), 7.78 (1H, dd, J=9.8, 1.8 Hz), 8.42 (1H,d, J=1.8 Hz), 9.97 (1H, d, J=2.7 Hz)

REFERENCE EXAMPLE 120

By the same technique as in Reference Example 101,3-fluoro-5-((methoxymethoxy)methyl)-2,6-dimethylpyridine was obtainedfrom 2,6-dichloro-3-fluoro-5-((methoxymethoxy)methyl)pyridine.

¹H-NMR (CDCl₃) δ: 2.47 (3H, s), 2.48 (3H, d, J=2.7 Hz), 3.42 (3H, s),4.55 (2H, s), 4.73 (2H, s), 7.35 (1H, d, J=9.8 Hz)

REFERENCE EXAMPLE 121

By the same technique as in Reference Example 102,(5-fluoro-2,6-dimethylpyridin-3-yl)methanol was obtained from3-fluoro-5-((methoxymethoxy)methyl)-2,6-dimethylpyridine.

¹H-NMR (CDCl₃) δ: 1.99-2.20 (1H, broad), 2.45 (3H, s), 2.48 (3H, d,J=2.9 Hz), 4.68 (2H, s), 7.40 (1H, d, J=9.8 Hz)

REFERENCE EXAMPLE 122

By the same technique as in Reference Example 103,5-fluoro-2,6-dimethylnicotinaldehyde was obtained from(5-fluoro-2,6-dimethylpyridin-3-yl)methanol.

¹H-NMR (CDCl₃) δ: 2.57 (3H, d, J=2.9 Hz), 2.82 (3H, d, J=1.0 Hz), 7.72(1H, d, J=9.0 Hz), 10.28 (1H, d, J=2.2 Hz)

REFERENCE EXAMPLE 123

To a solution of 0.25 g of(3,4-dihydro-2H-pyrano(2,3-c)pyridin-6-yl)methanol in 7.5 mL ofchloroform, 0.66 g of manganese dioxide was added, and the mixture washeated under reflux while stirring for 4 hours 50 minutes. The reactionmixture was cooled to room temperature, the insoluble substance was thenfiltered off, and the solvent was distilled off under reduced pressureto obtain 0.24 g of 3,4-dihydro-2H-pyrano(2,3-c)pyridine-6-carbaldehydeas a light yellow oily substance.

¹H-NMR (CDCl₃) δ: 2.04-2.11 (2H, m), 2.85 (2H, t, J=6.5 Hz), 4.32 (2H,t, J=5.1 Hz), 7.72 (1H, s), 8.27 (1H, s), 9.94 (1H, s)

REFERENCE EXAMPLE 124

By the same technique as in Reference Example 60, tert-butyl(3S)-3-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)pyrrolidine-1-carboxylatewas obtained from tert-butyl (3S)-3-aminopyrrolidine-1-carboxylate and2,3-dihydro(1,4)dioxino(2,3-c)pyridine-7-carbaldehyde.

¹H-NMR (CDCl₃) δ: 1.43 (9H, s), 1.54-1.64 (1H, m), 2.18-2.42 (2H, m),2.50-2.86 (3H, m), 3.62 (2H, s), 4.10-4.22 (1H, broad), 4.25-4.36 (4H,m), 4.86-4.94 (1H, m), 6.86 (1H, s), 8.10 (1H, s)

REFERENCE EXAMPLE 125

By the same technique as in Reference Example 13,(3S)—N-(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)pyrrolidin-3-aminehydrochloride was obtained from tert-butyl(3S)-3-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)pyrrolidine-1-carboxylate.

¹H-NMR (DMSO-d₆) δ: 2.03-2.14 (1H, m), 2.30-2.40 (1H, m), 3.30-3.72 (4H,m), 3.92-4.05 (1H, m), 4.32-4.43 (4H, m), 4.45 (2H, s), 7.19 (1H, s),8.22 (1H, s)

REFERENCE EXAMPLE 126

To 2.2 g of1-(1,3-dioxolan-2-ylmethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one, 20 mLof an 80% aqueous trifluoroacetic acid solution was added, and themixture was stirred at 80 to 90° C. for 3 hours. Thereto was added 10 mLof an 80% aqueous trifluoroacetic acid solution, and the mixture wasstirred at 80 to 90° C. for 2 hours, then, 10 mL of an 80% aqueoustrifluoroacetic acid solution was further added, and the mixture wasstirred at the same temperature for 9 hours. The reaction mixture wascooled to room temperature, and the solvent was then distilled off underreduced pressure. To the resultant residue, a 2 mol/L aqueous sodiumhydroxide solution was added and adjusted to pH 8.0, and chloroform andmethanol were added thereto. The organic layer was separated, and theaqueous layer was extracted with a mixed solution of chloroform andmethanol twice. The organic layer and the extract were combined, theresultant solution was dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure. Diethyl ether andhexane were added to the resultant residue, and the solid was filteredoff to obtain 1.5 g of7-fluoro-1-(2-hydroxy-2-methoxyethyl)-1,5-naphthyridin-2(1H)-one as alight brown solid.

¹H-NMR (DMSO-d₆) δ: 3.21 (3H, s), 4.19-4.31 (2H, m), 4.72-4.79 (1H, m),6.53 (1H, d, J=7.1 Hz), 6.84 (1H, d, J=9.8 Hz), 7.97 (1H, d, J=9.8 Hz),8.03 (1H, dd, J=11.5, 2.4 Hz), 8.55 (1H, d, J=2.4 Hz)

REFERENCE EXAMPLE 127

By the same technique as in Reference Example 77, tert-butyl(1-(2-(7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamatewas obtained from7-fluoro-1-(2-hydroxy-2-methoxyethyl)-1,5-naphthyridin-2(1H)-one andtert-butyl (piperidin-4-yl)carbamate.

¹H-NMR (CDCl₃) δ: 1.32-1.49 (2H, m), 1.44 (9H, s), 1.89-1.99 (2H, m),2.20-2.30 (2H, m), 2.61-2.68 (2H, m), 2.86-2.95 (2H, m), 3.42-3.54 (1H,m), 4.27-4.35 (2H, m), 4.38-4.47 (1H, m), 6.86 (1H, d, J=9.8 Hz),7.48-7.55 (1H, m), 7.89 (1H, d, J=9.8 Hz), 8.42 (1H, d, J=2.4 Hz)

REFERENCE EXAMPLE 128

By the same technique as in Reference Example 78,1-(2-(4-aminopiperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-onehydrochloride was obtained from tert-butyl(1-(2-(7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate.

¹H-NMR (D₂O) δ: 1.92-2.08 (2H, m), 2.34-2.45 (2H, m), 3.17-3.35 (2H, m),3.56-3.68 (3H, m), 3.91-4.03 (2H, m), 4.71-4.78 (2H, m), 6.99 (1H, d,J=9.9 Hz), 7.96 (1H, dd, J=10.0, 2.1 Hz), 8.09 (1H, d, J=9.9 Hz), 8.57(1H, d, J=2.1 Hz)

REFERENCE EXAMPLE 129

To a suspension of 0.40 g of7-bromo-1-((1,3-dioxolan-2-yl)methyl)-1,5-naphthyridin-2(1H)-one in 4 mLof dioxane, 0.18 g of tert-butyl carbamate, 0.59 g of cesium carbonate,22 mg of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, and 18 mg oftris(dibenzylideneacetone)dipalladium(0) were added at room temperature,and the mixture was stirred at 90 to 95° C. for 4 hour 15 minutes. Aftercooling to the room temperature, chloroform and water were added to thereaction mixture, the organic layer was separated, and washed with waterand a saturated aqueous sodium chloride solution. The organic layer wasdried over anhydrous magnesium sulfate, the solvent was distilled offunder reduced pressure, diethyl ether was added to the resultant residueand the solid was filtered off to obtain 0.29 g of tert-butyl(5-(1,3-dioxolan-2-yl)methyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)carbamateas a light yellow solid.

¹H-NMR (CDCl₃) δ: 1.55 (9H, s), 3.86-3.94 (2H, m), 4.02-4.13 (2H, m),4.46 (2H, d, J=4.6 Hz), 5.33 (1H, t, J=4.6 Hz), 6.80 (1H, d, J=9.6 Hz),6.91 (1H, s), 7.83 (1H, d, J=9.6 Hz), 8.29 (1H, d, J=2.0 Hz), 8.43 (1H,s)

REFERENCE EXAMPLE 130

To a solution of 0.15 g of tert-butyl(5-(1,3-dioxolan-2-yl)methyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)carbamatein 2 mL of N,N-dimethylformamide, 21 mg of 60% sodium hydride and 32 μLof methyl iodide were added, and the mixture was stirred at roomtemperature for 2 hours 20 minutes. Thereto were further added 9 mg of60% sodium hydride and 13 μL of methyl iodide, and the mixture wasstirred at room temperature for 1 hour. Ethyl acetate and water wereadded to the reaction mixture, and the organic layer was separated. Theorganic layer was washed with a saturated aqueous sodium chloridesolution and dried over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure. The resultant residue was purifiedby flash silica gel column chromatography using gradient elution withhexane:ethyl acetate=1:1 to 3:7 to obtain 0.13 g of tert-butyl(5-(1,3-dioxolan-2-yl)methyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)(methyl)carbamateas a brown oily substance.

¹H-NMR (CDCl₃) δ: 1.50 (9H, s), 3.38 (3H, s), 3.85-3.94 (2H, m),3.97-4.05 (2H, m), 4.48 (2H, d, J=4.3 Hz), 5.22 (1H, t, J=4.3 Hz), 6.87(1H, d, J=9.8 Hz), 7.84-7.89 (2H, m), 8.51 (1H, d, J=2.0 Hz)

REFERENCE EXAMPLE 131

To a solution of 10 g of5-(benzyloxy)-2-(hydroxymethyl)pyridin-4(1H)-one in 58 mL of pyridine,4.6 mL of acetyl chloride was added under cooling with ice, and themixture was stirred at 60 to 70° C. for 3 hours. The solvent wasdistilled off under reduced pressure, water was added thereto, and themixture was stirred under cooling with ice. The solid was filtered off,chloroform was added thereto and the resultant was dried over anhydrousmagnesium sulfate, the solvent was distilled off under reduced pressure.Thereto was added diethyl ether and the solid was filtered off to obtain9.2 g of (5-(benzyloxy)-4-oxo-1,4-dihydropyridin-2-yl)methyl acetate asa light brown solid.

¹H-NMR (CDCl₃) δ: 2.08 (3H, s), 4.89 (2H, s), 5.00 (2H, s), 6.63 (1H,s), 7.28 (5H, s), 7.50 (1H, s)

REFERENCE EXAMPLE 132

To a solution of 6.1 g of(5-(benzyloxy)-4-oxo-1,4-dihydropyridin-2-yl)methyl acetate in 50 mL ofdimethyl sulfoxide, 5.0 g of tert-butyl (2-bromoethyl)carbamate and 10 gof potassium carbonate were added, and the mixture was stirred at 80 to90° C. for 6 hours 30 minutes. The reaction mixture was cooled to roomtemperature, and ethyl acetate and water were then added thereto. Theorganic layer was separated, washed with water and dried over anhydrousmagnesium sulfate, and the solvent was distilled off under reducedpressure. The resultant residue was purified by flash silica gel columnchromatography using gradient elution with chloroform:methanol=99:1 to98:2 obtain 3.8 g of(5-(benzyloxy)-4-(2-((tert-butoxycarbonyl)amino)ethoxy)pyridin-2-yl)methylacetate as a brown oily substance.

¹H-NMR (CDCl₃) δ: 1.45 (9H, s), 2.15 (3H, s), 3.58 (2H, q, J=5.3 Hz),4.13 (2H, t, J=5.3 Hz), 4.96 (1H, s), 5.10 (2H, s), 5.16 (2H, s), 6.89(1H, s), 7.30-7.45 (5H, m), 8.16 (1H, s)

REFERENCE EXAMPLE 133

To a solution of 3.8 g of(5-(benzyloxy)-4-(2-((tert-butoxycarbonyl)amino)ethoxy)pyridin-2-yl)methylacetate in 91 mL of ethanol, 1.1 g of 10% palladium carbon was added,and the mixture was stirred at room temperature for 5 hours under ahydrogen atmosphere. The insoluble substance was filtered off, and thesolvent was distilled off under reduced pressure. Thereto were addedchloroform and diethyl ether, and the solid was filtered off to obtain2.1 g of(4-(2-((tert-butoxycarbonyl)amino)ethoxy)-5-hydroxypyridin-2-yl)methylacetate as a light brown solid.

¹H-NMR (CDCl₃) δ: 1.45 (9H, s), 2.15 (3H, s), 3.61 (2H, q, J=4.8 Hz),4.21 (2H, t, J=4.8 Hz), 5.20 (2H, s), 5.35 (1H, s), 6.94 (1H, s), 8.26(1H, s)

REFERENCE EXAMPLE 134

To a solution of 1.0 g of(4-(2-((tert-butoxycarbonyl)amino)ethoxy)-5-hydroxypyridin-2-yl)methylacetate in 15 mL of dichloromethane, 0.86 mL of triethylamine and 0.78mL of trifluoromethanesulfonic anhydride were added under cooling withice, and the mixture was stirred for 30 minutes. Thereto were added asaturated aqueous sodium hydrogen carbonate solution and water, and theorganic layer was separated and washed with a saturated aqueous sodiumchloride solution. The organic layer was dried over anhydrous magnesiumsulfate and the solvent was distilled off under reduced pressure. Theresultant residue was purified by flash silica gel column chromatographyusing gradient elution with hexane:ethyl acetate=66:34 to 50:50 toobtain 1.3 g of(4-(2-((tert-butoxycarbonyl)amino)ethoxy)-5-(((trifluoromethyl)sulfonyl)oxy)pyridin-2-yl)methylacetate as a colorless oily substance.

¹H-NMR (CDCl₃) δ: 1.45 (9H, s), 2.20 (3H, s), 3.60 (2H, q, J=5.2 Hz),4.23 (2H, t, J=5.2 Hz), 5.05 (1H, s), 5.18 (2H, s), 7.04 (1H, s), 8.35(1H, s)

REFERENCE EXAMPLE 135

To a solution of 1.0 g of(4-(2-((tert-butoxycarbonyl)amino)ethoxy)-5-(((trifluoromethyl)sulfonyl)oxy)pyridin-2-yl)methylacetate in 5.0 mL of dioxane, 1.0 g of cesium carbonate, 58 mg oftris(dibenzylideneacetone)dipalladium (0) and 76 mg of4,5-bis(diphenylphosphino)-9,9-dimethylxanthene were added, and themixture was heated under reflux while stirring for 2 hours. Ethylacetate was added to the reaction mixture, the insoluble substance wasfiltered off, and the solvent was distilled off under reduced pressure.The resultant residue was purified by flash silica gel columnchromatography using gradient elution with hexane:ethyl acetate=60:40 to0:100 to obtain 0.29 g of tert-butyl7-((acetoxy)methyl)-2,3-dihydro-4H-pyrido(4,3-b)(1,4)oxadine-4-carboxylateas a brown solid.

¹H-NMR (CDCl₃) δ: 1.56 (9H, s), 2.14 (3H, s), 3.85-3.89 (2H, m),4.29-4.32 (2H, m), 5.11 (2H, s), 6.86 (1H, s), 8.88 (1H, s)

REFERENCE EXAMPLE 136

To a solution of 0.11 g of tert-butyl7-((acetoxy)methyl)-2,3-dihydro-4H-pyrido(4,3-b)(1,4)oxadine-4-carboxylatein a mixture of 1.7 mL of tetrahydrofuran and 1.7 mL of water, 0.36 mLof a 2.0 mol/L aqueous sodium hydroxide solution was added, and themixture was stirred at room temperature for 1 hour. The reactionsolution was saturated with potassium carbonate, ethyl acetate was thenadded thereto, the organic layer was separated and the aqueous layer wasextracted with ethyl acetate. The organic layer and the extract werecombined, the resultant solution was washed with a saturated aqueoussodium chloride solution and dried over anhydrous magnesium sulfate, andthe solvent was distilled off under reduced pressure to obtain 90 mg oftert-butyl7-(hydroxymethyl)-2,3-dihydro-4H-pyrido(4,3-b)(1,4)oxadine-4-carboxylateas a brown oily substance.

¹H-NMR (CDCl₃) δ: 1.56 (9H, s), 3.32-3.41 (1H, m), 3.86-3.89 (2H, m),4.29-4.32 (2H, m), 4.64 (2H, s), 6.76 (1H, s), 8.82-8.89 (1H, m)

REFERENCE EXAMPLE 137

By the same technique as in Reference Example 67, tert-butyl7-formyl-2,3-dihydro-4H-pyrido(4,3-b)(1,4)oxadine-4-carboxylate wasobtained from tert-butyl7-(hydroxymethyl)-2,3-dihydro-4H-pyrido(4,3-b)(1,4)oxadine-4-carboxylate.

¹H-NMR (CDCl₃) δ: 1.58 (9H, s), 3.91-3.94 (2H, m), 4.34-4.37 (2H, m),7.48 (1H, s), 9.12-9.21 (1H, m), 9.96 (1H, s)

REFERENCE EXAMPLE 138

To a solution of 0.30 g of8-(2-hydroxyethyl)-1,4-dioxaspiro(4.5)decan-8-al in 5 mL ofdichloromethane, 0.76 g of Dess-Martin periodinane was added undercooling with ice, and the mixture was stirred at room temperature for 1hour. To the reaction mixture, water was added under cooling with ice,and the organic layer was separated, and the aqueous layer was extractedwith chloroform. The organic layer and the extract were combined, andthe resultant solution was washed with a saturated aqueous sodiumchloride solution, and dried over anhydrous magnesium sulfate. Thesolvent was distilled off under reduced pressure, chloroform was addedthereto, and the insoluble substance was filtered off. The resultantresidue was purified by flash silica gel column chromatography usinggradient elution with hexane:ethyl acetate=35:65 to 25:75 to obtain 0.19g of (8-hydroxy-1,4-dioxaspiro(4.5)deca-8-yl)acetaldehyde as a slightlyyellow oily substance.

¹H-NMR (CDCl₃) δ: 1.53-1.64 (2H, m), 1.68 (2H, td, J 13.1, 4.3 Hz),1.79-1.89 (2H, m), 1.95 (2H, dt, J=12.7, 4.3 Hz), 2.54-2.59 (1H, broad),2.65 (2H, d, J=1.5 Hz), 3.90-4.00 (4H, m), 9.88 (1H, t, J=1.5 Hz)

REFERENCE EXAMPLE 139

To a solution of 150 g of 2-chloro-5-fluoropyridin-3-amine in 600 mL ofN,N-dimethylformamide, 190 mL of butyl acrylate and 287 mL oftriethylamine were added under a nitrogen flow, and the mixture wasstirred at 110° C. for 2 hours. The reaction mixture was cooled to 58°C., thereto were added 13.1 g ofbis(tri-tert-butylphosphine)palladium(0), and the mixture was stirred at110 to 120° C. for 40 minutes. The reaction mixture was cooled to 57°C., 13.1 g of bis(tri-tert-butylphosphine)palladium(0) was addedthereto, and the mixture was stirred at 110 to 120° C. for 3 hours. Thereaction mixture was cooled to room temperature, and water and ethylacetate were added thereto. The insoluble substance was filtered off,the organic layer of the filtrate was separated, and the aqueous layerwas extracted with ethyl acetate. The organic layer and the extract werecombined, the resultant solution was washed sequentially with water anda saturated aqueous sodium chloride solution and dried over anhydrousmagnesium sulfate, and the solvent was distilled off under reducedpressure. Cyclohexane and ethyl acetate were added to the resultantresidue, and the solid was filtered off to obtain 200 g of butyl(2E)-3-(3-amino-5-fluoropyridin-2-yl)acrylate as a light brown solid.

¹H-NMR (CDCl₃) δ: 0.95 (3H, t, J=7.3 Hz), 1.38-1.48 (2H, m), 1.64-1.72(2H, m), 4.13 (2H, s), 4.21 (2H, t, J=6.7 Hz), 6.71 (1H, dd, J=9.8, 2.3Hz), 6.86 (1H, d, J=15.3 Hz), 7.72 (1H, d, J=15.3 Hz), 7.94 (1H, d,J=2.3 Hz)

REFERENCE EXAMPLE 140

To a solution of 90 mg of butyl(2E)-3-(3-amino-5-fluoropyridin-2-yl)acrylate in 5 mL ofdichloromethane, 90 mg of(8-hydroxy-1,4-dioxaspiro(4.5)deca-8-yl)acetaldehyde and 33 μL of aceticacid were added, and the mixture was stirred at room temperature for 4hours and left overnight. To the reaction mixture, 80 mg of sodiumtriacetoxyborohydride was added, and the mixture was stirred at roomtemperature for 1 hour. Thereto were added a saturated aqueous sodiumhydrogen carbonate solution and chloroform, the organic layer wasseparated, and the aqueous layer was extracted with chloroform. Theorganic layer and the extract were combined, the resultant solution waswashed with a saturated aqueous sodium chloride solution and dried overanhydrous magnesium sulfate, and the solvent was distilled off underreduced pressure. The resultant residue was purified by flash silica gelcolumn chromatography using gradient elution with hexane:ethylacetate=60:40 to 50:50 to obtain 82 mg of butyl(2E)-3-(5-fluoro-3-((2-(8-hydroxy-1,4-dioxaspiro(4.5)deca-8-yl)ethyl)amino)pyridin-2-yl)acrylateas a yellow oily substance.

¹H-NMR (CDCl₃) δ: 0.95 (3H, t, J=7.4 Hz), 1.38-1.48 (2H, m), 1.55-2.00(10H, m), 3.22-3.30 (2H, m), 3.90-4.02 (6H, m), 4.20 (2H, t, J=6.6 Hz),5.40-5.47 (1H, m), 6.63 (1H, dd, J=11.2, 2.4 Hz), 6.83 (1H, d, J=15.2Hz), 7.71 (1H, d, J=15.2 Hz), 7.82 (1H, d, J=2.4 Hz)

REFERENCE EXAMPLE 141

To a solution of 80 mg of butyl(2E)-3-(5-fluoro-3-((2-(8-hydroxy-1,4-dioxaspiro(4.5)deca-8-yl)ethyl)amino)pyridin-2-yl)acrylatein 4 mL of a mixture of methanol and tetrahydrofuran (1:1), 55 mg of a28% sodium methoxide/methanol solution was added at room temperature,and the mixture was heated under reflux while stirring for 1 hour. Thereaction mixture was cooled to room temperature, then, ethyl acetate andwater were added thereto, and the organic layer was separated. Theorganic layer was washed with a saturated aqueous sodium chloridesolution, and dried over anhydrous magnesium sulfate, and the solventwas distilled off under reduced pressure to obtain 65 mg of1-(2-(8-hydroxy-1,4-dioxaspiro(4.5)deca-8-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-oneas a yellow oily substance.

¹H-NMR (CDCl₃) δ: 1.70-1.80 (4H, m), 1.87-1.96 (4H, m), 2.48-2.56 (2H,m), 3.92-4.00 (4H, m), 3.98 (3H, s), 4.38-4.45 (2H, m), 6.76 (1H, d,J=9.8 Hz), 7.24-7.32 (1H, m), 7.87 (1H, d, J=9.8 Hz), 8.30 (1H, d, J=2.4Hz)

REFERENCE EXAMPLE 142

To 60 mg of1-(2-(8-hydroxy-1,4-dioxaspiro(4.5)deca-8-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-one,3 mL of an 80% aqueous trifluoroacetic acid solution was added at roomtemperature, and the mixture was stirred for 8 hours 30 minutes. Thesolvent was distilled off under reduced pressure to the resultantresidue, a saturated aqueous sodium hydrogen carbonate solution andethyl acetate were added, the organic layer was separated, and theaqueous layer was extracted with ethyl acetate. The organic layer andthe extract were combined, and the resultant solution was washed with asaturated aqueous sodium chloride solution, and dried over anhydrousmagnesium sulfate. The solvent was distilled off under reduced pressure,and the resultant residue was purified by flash silica gel columnchromatography using gradient elution with chloroform:methanol=100:0 to99:1 to obtain 41 mg of1-(2-(1-hydroxy-4-oxocyclohexyl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-oneas a yellow solid.

¹H-NMR (CDCl₃) δ: 1.60-2.12 (6H, m), 2.22-2.30 (2H, m), 2.73-2.83 (2H,m), 3.67-3.76 (1H, broad), 4.00 (3H, s), 4.47 (2H, t, J=6.7 Hz), 6.80(1H, d, J=9.6 Hz), 7.16 (1H, d, J=2.3 Hz), 7.93 (1H, d, J=9.6 Hz), 8.35(1H, d, J=2.3 Hz)

REFERENCE EXAMPLE 143

To a solution of 0.50 g of 1-(trifluoroacetyl)piperidin-4-amine in 10 mLof a mixed solvent of N,N-dimethylformamide and tetrahydrofuran (1:1),0.41 g of potassium carbonate, 0.42 mL of propargyl bromide were added,and the mixture was heated under reflux while stirring for 2 hours.Thereto were added water and ethyl acetate, the organic layer wasseparated, and the aqueous layer was extracted with ethyl acetate. Theorganic layer and the extract were combined, the resultant solution waswashed with water and a saturated aqueous sodium chloride solution, anddried over anhydrous magnesium sulfate, and the solvent was distilledoff under reduced pressure to obtain 0.60 g ofN-(2-propyn-1-yl)-1-(trifluoroacetyl)piperidin-4-amine as a crudeproduct (crude product A). On the other hand, to a solution of 0.70 g of1-(trifluoroacetyl)piperidin-4-amine in 7.2 mL of a mixed solvent ofN,N-dimethylformamide and tetrahydrofuran (1:1), 0.59 g of potassiumcarbonate, and 0.30 mL of propargyl bromide were added, and the mixturewas heated under reflux while stirring for 1 hour 50 minutes. Theretowere added water and ethyl acetate, and mixed with 0.60 g of the crudeproduct A obtained above, and the mixture was adjusted to pH 1 with 6mol/L hydrochloric acid. The aqueous layer was separated, and washedwith ethyl acetate, ethyl acetate was added thereto, and the aqueouslayer was saturated with potassium carbonate. The organic layer wasseparated, washed with a saturated aqueous sodium chloride solution, anddried over anhydrous magnesium sulfate, and the solvent was distilledoff under reduced pressure to obtain 1.0 g ofN-(2-propyn-1-yl)-1-(trifluoroacetyl)piperidin-4-amine as a brown oilysubstance.

¹H-NMR (CDCl₃) δ: 1.36-1.48 (2H, m), 1.90-1.98 (2H, m), 2.23 (1H, t,J=2.3 Hz), 3.03-3.34 (3H, m), 3.48 (2H, d, J=2.3 Hz), 3.90-3.98 (1H, m),4.22-4.31 (1H, m)

REFERENCE EXAMPLE 144

(1) To a solution of 0.60 g ofN-(2-propyn-1-yl)-1-(trifluoroacetyl)piperidin-4-amine in 5.2 mL ofdioxane, 0.56 g of di-tert-butyl dicarbonate was added and the mixturewas stirred at room temperature for 1 hour 45 minutes. The solvent wasdistilled off under reduced pressure, and the resultant residue waspurified by silica gel column chromatography using an elution withhexane:ethyl acetate=3:1 to obtain 0.70 g of tert-butyl(2-propyn-1-yl)(1-(trifluoroacetyl)piperidin-4-yl)carbamate as acolorless oily substance.

(2) To a solution of 0.20 g of tert-butyl(2-propyn-1-yl)(1-(trifluoroacetyl)piperidin-4-yl)carbamate in 6.0 mL oftriethylamine, 59 μL of iodopyrazine, 0.57 mg of copper (I) iodide, and4.2 mg of dichlorobis(triphenylphosphine)palladium(II) were added undera nitrogen atmosphere, and the mixture was stirred at 60 to 70° C. for 4hours 30 minutes. The insoluble substance was filtered off, and thesolvent was distilled off under reduced pressure. The resultant residuewas purified by flash silica gel column chromatography using gradientelution with hexane:ethyl acetate=60:40 to 50:50 to obtain 0.17 g oftert-butyl(3-(pyrazin-2-yl)-2-propyn-1-yl)(1-(trifluoroacetyl)piperidin-4-yl)carbamateas a colorless oily substance.

¹H-NMR (CDCl₃) δ: 1.51 (9H, s), 1.76-2.02 (4H, m), 2.72-2.84 (1H, m),3.12-3.22 (1H, m), 4.08-4.26 (4H, m), 4.64-4.72 (1H, m), 8.49 (1H, d,J=2.7 Hz), 8.53-8.56 (1H, m), 8.60 (1H, d, J=1.2 Hz)

REFERENCE EXAMPLE 145

By the same technique as in Reference Example 62, tert-butyl(piperidin-4-yl)(3-pyrazin-2-yl)-2-propyn-1-yl)carbamate was obtainedfrom tert-butyl(3-(pyrazin-2-yl)-2-propyn-1-yl)(1-(trifluoroacetyl)piperidin-4-yl)carbamate.

¹H-NMR (CDCl₃) δ: 1.51 (9H, s), 1.72-1.92 (4H, m), 2.66-2.76 (2H, m),3.17-3.24 (2H, m), 3.96-4.30 (3H, m), 8.47 (1H, d, J=2.4 Hz), 8.51-8.54(1H, m), 8.62 (1H, d, J=1.2 Hz)

REFERENCE EXAMPLE 146

By the same technique as in Reference Example 140, ethyl(2E)-3-(3-((2-(8-hydroxy-1,4-dioxaspiro(4.5)deca-8-yl)ethyl)amino)-5-methoxypyrazin-2-yl)acrylatewas obtained from 8-hydroxy-1,4-dioxaspiro(4.5)deca-8-yl)acetaldehydeand ethyl (2E)-3-(3-amino-5-methoxypyrazin-2-yl)acrylate.

¹H-NMR (CDCl₃) δ: 1.31 (3H, t, J=7.2 Hz), 1.71-1.90 (8H, m), 3.60-3.65(2H, m), 3.90-4.00 (6H, m), 3.94 (3H, s), 4.24 (2H, q, J=7.2 Hz),5.80-5.94 (1H, m), 6.68 (1H, d, J=15.1 Hz), 7.51 (1H, s), 7.63 (1H, d,J=15.1 Hz)

REFERENCE EXAMPLE 147

By the same technique as in Reference Example 2,5-(2-(8-hydroxy-1,4-dioxaspiro(4.5)deca-8-yl)ethyl)-3-methoxypyrido(2,3-b)pyrazin-6(5H)-onewas obtained from ethyl(2E)-3-(3-((2-(8-hydroxy-1,4-dioxaspiro(4.5)deca-8-yl)ethyl)amino)-5-methoxypyrazin-2-yl)acrylate.

¹H-NMR (CDCl₃) δ: 1.50-1.80 (6H, m), 1.90-2.00 (4H, m), 2.40-2.44 (1H,broad), 3.89-3.99 (4H, m), 4.08 (3H, s), 4.58-4.62 (2H, m), 6.78 (1H, d,J=9.6 Hz), 7.87 (1H, d, J=9.6 Hz), 8.14 (1H, s)

REFERENCE EXAMPLE 148

By the same technique as in Reference Example 142,5-(2-(1-hydroxy-4-oxocyclohexyl)ethyl)-3-methoxypyrido(2,3-b)pyrazin-6(5H)-onewas obtained from5-(2-(8-hydroxy-1,4-dioxaspiro(4.5)deca-8-yl)ethyl)-3-methoxypyrido(2,3-b)pyrazin-6(5H)-one.

¹H-NMR (CDCl₃) δ: 1.79 (2H, td, J=13.8, 4.9 Hz), 2.04 (2H, t, J=6.8 Hz),2.03-2.12 (2H, m), 2.20-2.29 (2H, m), 2.80 (2H, td, J=13.8, 6.2 Hz),3.30-3.45 (1H, broad), 4.09 (3H, s), 4.65 (2H, t, J=6.8 Hz), 6.81 (1H,d, J=9.6 Hz), 7.92 (1H, d, J=9.6 Hz), 8.18 (1H, s)

REFERENCE EXAMPLE 149

To a solution of 0.28 g of tert-butyl3-(aminomethyl)pyrrolidine-1-carboxylate in a mixture of 7 mL ofmethanol and 20 mL of dichloromethane, 0.23 g of2,3-dihydro(1,4)dioxino(2,3-c)pyridine-7-carbaldehyde and 0.50 g ofmolecular sieves 3 A were added, the mixture was stirred at roomtemperature for 3 hours, and then, the reaction mixture was charged with79 mg of sodium borohydride and stirred at room temperature for 5 hours30 minutes. Thereto was added water under cooling with ice, the organiclayer was separated, and the aqueous layer was extracted withchloroform. The organic layer and the extract were combined, theresultant solution was washed with a saturated aqueous sodium chloridesolution and dried over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure to obtain 0.48 g of tert-butyl3-(((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)methyl)pyrrolidine-1-carboxylateas a colorless oily substance.

¹H-NMR (CDCl₃) δ: 1.45 (9H, s), 1.50-3.60 (9H, m), 3.77 (2H, s),4.26-4.36 (4H, m), 6.81 (1H, s), 8.11 (1H, s)

REFERENCE EXAMPLE 150

By the same technique as in Reference Example 13,1-(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-yl)-N-(pyrrolidin-3-ylmethyl)methanaminehydrochloride was obtained from tert-butyl3-(((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)methyl)pyrrolidine-1-carboxylate.

¹H-NMR (D₂O) δ: 1.76-1.89 (1H, m), 2.31-2.41 (1H, m), 2.73-2.87 (1H, m),3.02-3.11 (1H, m), 3.28-3.40 (3H, m), 3.45-3.54 (1H, m), 3.64 (1H, dd,J=11.8, 8.2 Hz), 4.41-4.49 (4H, m), 4.54-4.60 (2H, m), 7.35-7.46 (1H,m), 8.30-8.36 (1H, m)

REFERENCE EXAMPLE 151

A solution of 2.0 g of 7-methyl-1,8-naphthyridin-2(1H)-one in 150 mL ofethanol, 1.0 g of 5% palladium-carbon was added, and the mixture wasstirred at 40 to 50° C. for 17 hours under a hydrogen atmosphere. Thereaction mixture was cooled to room temperature, the insoluble substancewas filtered off, and the filtration residue was washed with methanol.The solvent was distilled off under reduced pressure, and the resultantresidue was purified by silica gel column chromatography using an eluentof hexane:ethyl acetate=1:1 to obtain 0.92 g of7-methyl-3,4-dihydro-1,8-naphthyridin-2(1H)-one as a white solid.

¹H-NMR (CDCl₃) δ: 2.52 (3H, s), 2.61-2.68 (2H, m), 2.86-2.94 (2H, m),6.78 (1H, d, J=7.6 Hz), 7.36 (1H, d, J=7.6 Hz), 9.86 (1H, s)

REFERENCE EXAMPLE 152

A solution of 0.90 g of 7-methyl-3,4-dihydro-1,8-naphthyridin-2(1H)-onein 150 mL of dioxane was heated under reflux while dividedly adding 25.7g of selenium dioxide, and the mixture was stirred for 10 days. Theinsoluble substance was filtered off with celite, and the solvent wasdistilled off under reduced pressure. To the resultant residue,2-propanol was added, and the solid was filtered off. The solid thusobtained was purified by silica gel column chromatography using aneluent of chloroform:methanol=20:1, and ethyl acetate was added thereto,and the solid was filtered off to obtain 0.48 g of7-oxo-7,8-dihydro-1,8-naphthyridine-2-carbaldehyde as a light orangesolid.

¹H-NMR (CDCl₃) δ: 6.87 (1H, d, J=9.6 Hz), 7.80 (1H, d, J=9.6 Hz), 7.85(1H, dd, J=7.8, 1.0 Hz), 8.07 (1H, d, J=7.8 Hz), 10.11 (1H, s)

REFERENCE EXAMPLE 153

To a solution of 0.53 g of 1-(trifluoroacetyl)piperidin-4-amine in 100mL of dichloromethane, 0.47 g of7-oxo-7,8-dihydro-1,8-naphthyridine-2-carbaldehyde and 0.16 mL of aceticacid were added, and the mixture was stirred at room temperature for 45minutes. The reaction mixture was added with 0.86 g of sodiumtriacetoxyborohydride and stirred at the same temperature for 5 hours.Thereto were added water, a saturated aqueous sodium hydrogen carbonatesolution and chloroform, the organic layer was separated, and theaqueous layer was extracted with chloroform. Sodium chloride was furtheradded to the aqueous layer, and the aqueous layer was extracted withchloroform. The organic layer and the extract were combined, theresultant solution was dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure. The resultant residuewas purified by silica gel column chromatography using an eluent ofchloroform:methanol=20:1 to obtain 0.59 g of7-(((1-(trifluoroacetyl)piperidin-4-yl)amino)methyl)-1,8-naphthyridin-2(1H)-oneas a light orange foam.

¹H-NMR (CDCl₃) δ: 1.42-1.56 (2H, m), 1.98-2.08 (2H, m), 2.85-2.94 (1H,m), 3.01-3.11 (1H, m), 3.19-3.29 (1H, m), 3.93-4.02 (1H, m), 4.06 (2H,s), 4.29-4.38 (1H, m), 6.70 (1H, d, J=9.4 Hz), 7.24 (1H, d, J=7.8 Hz),7.72 (1H, d, J=9.4 Hz), 7.86 (1H, d, J=7.8 Hz)

REFERENCE EXAMPLE 154

To a solution of 0.58 g of7-(((1-(trifluoroacetyl)piperidin-4-yl)amino)methyl)-1,8-naphthyridin-2(1H)-onein 25 mL of chloroform, 0.43 g of di-tert-butyl dicarbonate was added,and the mixture was stirred at room temperature for 3 days. Water wasadded to the reaction mixture, the organic layer was separated, and theaqueous layer was extracted with chloroform. The organic layer and theextract were combined, the resultant solution was washed with asaturated aqueous sodium chloride solution, and dried over anhydrousmagnesium sulfate, the solvent was distilled off under reduced pressure,and a mixed solvent of hexane:ethyl acetate (1:1) was added thereto, andthe solid was filtered off to obtain 0.56 g of tert-butyl((7-oxo-7,8-dihydro-1,8-naphthyridin-2-yl)methyl)(1-(trifluoroacetyl)piperidin-4-yl)carbamateas a light pinkish white solid.

¹H-NMR (CDCl₃) δ: 1.29-2.00 (13H, m), 2.67-2.84 (1H, m), 3.06-3.24 (1H,m), 4.06-4.20 (2H, m), 4.35-4.67 (3H, m), 6.69 (1H, d, J=9.5 Hz),7.04-7.19 (1H, m), 7.70 (1H, d, J=9.5 Hz), 7.85 (1H, d, J=8.0 Hz), 9.69(1H, s)

REFERENCE EXAMPLE 155

To a solution of 0.30 g of tert-butyl((7-oxo-7,8-dihydro-1,8-naphthyridin-2-yl)methyl)(1-(trifluoroacetyl)piperidin-4-yl)carbamatein 40 mL of methanol, 0.10 g of 10% palladium-carbon was added, and themixture was stirred at 45 to 50° C. for 9 hours 30 minutes under ahydrogen atmosphere. The reaction mixture was cooled to roomtemperature, the insoluble substance was filtered off, and thefiltration residue was washed with methanol. The solvent was distilledoff under reduced pressure, and the resultant residue was purified bysilica gel column chromatography using an eluent ofchloroform:methanol=100:3 to obtain 0.18 g of tert-butyl((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)methyl)(1-(trifluoroacetyl)piperidin-4-yl)carbamateas a colorless foam.

¹H-NMR (CDCl₃) δ: 1.24-1.88 (13H, m), 2.59-2.81 (3H, m), 2.87-2.98 (2H,m), 3.04-3.20 (1H, m), 3.98-4.08 (1H, m), 4.26-4.48 (3H, m), 4.54-4.63(1H, m), 6.76-6.92 (1H, m), 7.43 (1H, d, J=7.6 Hz), 8.20-8.60 (1H,broad)

REFERENCE EXAMPLE 156

To a solution of 0.30 g of tert-butyl((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)methyl)(1-(trifluoroacetyl)piperidin-4-yl)carbamatein 12 mL of methanol, 0.10 g of potassium carbonate and 3 mL of waterwere added, and the mixture was stirred at room temperature for 7 hours30 minutes. To the reaction mixture, water, a saturated aqueous sodiumhydrogen carbonate solution and chloroform were added, the organic layerwas separated, and the aqueous layer was added with sodium chloride andextracted with chloroform. The organic layer and the extract werecombined, the resultant solution was washed with a saturated aqueoussodium chloride solution and dried over anhydrous magnesium sulfate, andthe solvent was distilled off under reduced pressure to obtain 0.24 g oftert-butyl((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)methyl)(piperidin-4-yl)carbamateas a colorless foam.

¹H-NMR (CDCl₃) δ: 1.28-1.78 (13H, m), 2.55-2.72 (4H, m), 2.87-2.97 (2H,m), 3.02-3.12 (2H, m), 4.15-4.50 (3H, m), 6.80-6.91 (1H, m), 7.41 (1H,d, J=7.6 Hz), 8.00-8.30 (1H, broad)

REFERENCE EXAMPLE 157

To a solution of 0.13 g of (4-methoxy-5-methylpyridin-2-yl)methanol in 2mL of dichloromethane, 0.14 g of manganese dioxide was added. Themixture was stirred for 6 hours while dividedly further adding 0.36 g ofmanganese dioxide at room temperature. The insoluble substance wasfiltered off, the solvent was distilled off under reduced pressure, andthe resultant residue was purified by flash column chromatography usinggradient elution of hexane:ethyl acetate=9:1 to 4:1 to obtain 77 mg of4-methoxy-5-methylpyridine-2-carbaldehyde as a white solid.

¹H-NMR (CDCl₃) δ: 2.26 (3H, s), 3.95 (3H, s), 7.43 (1H, s), 8.42 (1H,s), 10.00 (1H, s)

REFERENCE EXAMPLE 158

To a solution of 49 mg of (5-ethyl-4-methoxypyridin-2-yl)methanol in 1mL of dichloromethane, 0.13 g of manganese dioxide was added. Themixture was stirred at room temperature for 1 hour 30 minutes, 0.13 g ofmanganese dioxide was then added thereto, and the mixture was stirredfor 1 hour 30 minutes. Chloroform was added to the reaction mixture, theinsoluble substance was filtered off, and the solvent was distilled offunder reduced pressure to obtain 54 mg of5-ethyl-4-methoxypyridine-2-carbaldehyde as a brown oily substance.

¹H-NMR (CDCl₃) δ: 1.24 (3H, t, J=7.5 Hz), 2.70 (2H, q, J=7.5 Hz), 3.95(3H, s), 7.45 (1H, s), 8.43 (1H, s), 10.00 (1H, s)

REFERENCE EXAMPLE 159

To a suspension of 8.3 g of 2-(hydroxymethyl)-5-methoxypyridin-4(1H)-onein 30 mL of pyridine, 5.7 mL of acetyl chloride was dropped undercooling with ice. After warming to room temperature, the mixture wasstirred at 55 to 60° C. for 2 hours 30 minutes. After cooling to roomtemperature, the solvent was distilled off under reduced pressure, andthe resultant residue was purified by flash silica gel columnchromatography using gradient elution with chloroform:methanol=95:1 to80:20 to obtain 6.7 g of (5-methoxy-4-oxo-1,4-dihydropyridin-2-yl)methylacetate as a brown foam.

¹H-NMR (CDCl₃) δ: 2.15 (3H, s), 3.86 (3H, s), 5.15 (2H, s), 6.83 (1H,s), 7.68 (1H, s)

REFERENCE EXAMPLE 160

To a solution of 4.6 g of(5-methoxy-4-oxo-1,4-dihydropyridin-2-yl)methyl acetate in 120 mL ofdichloromethane, 6.5 mL of triethylamine was added, 5.9 mL oftrifluoromethanesulfonic anhydride was dropped under cooling with ice,and the mixture was stirred at the same temperature for 3 hours. Waterand the chloroform were added to the reaction mixture, the organic layerwas separated, and the aqueous layer was extracted with chloroform. Theorganic layer and the extract were combined, the resultant solution wasdried over anhydrous magnesium sulfate, and the solvent was distilledoff under reduced pressure. The resultant residue was purified by flashsilica gel column chromatography using gradient elution withhexane:ethyl acetate=4:1 to 4:6 to obtain 5.2 g of(5-methoxy-4-(((trifluoromethyl)sulfonyl)oxy)pyridin-2-yl)methyl acetateas a yellow solid.

¹H-NMR (CDCl₃) δ: 2.16 (3H, S), 4.03 (3H, s), 5.18 (2H, s), 7.26 (1H,s), 8.43 (1H, s)

REFERENCE EXAMPLE 161

To a solution of 0.50 g of(5-methoxy-4-(((trifluoromethyl)sulfonyl)oxy)pyridin-2-yl)methyl acetatein 5 mL of dioxane, 0.63 g of potassium carbonate, 0.21 mL oftrimethylboroxin and 0.18 g of tetrakis(triphenylphosphine)palladium(0)were added, and the mixture was stirred at 70 to 90° C. for 3 hoursunder a nitrogen atmosphere. The mixture was heated under reflux whilefurther stirring for 3 hours, after cooling to room temperature, waterand ethyl acetate were added to the reaction mixture, and the organiclayer was separated. The aqueous layer was extracted with ethyl acetate,the organic layer and the extract were combined, the resultant solutionwas dried over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure. The resultant residue was purifiedby flash silica gel column chromatography using gradient elution withhexane:ethyl acetate=80:20 to 50:50 to obtain 0.22 g of(5-methoxy-4-methylpyridin-2-yl)methyl acetate as a yellow oilysubstance.

¹H-NMR (CDCl₃) δ: 2.13 (3H, s), 2.23 (3H, s), 3.92 (3H, s), 5.12 (2H,s), 7.15 (1H, s), 8.14 (1H, s)

REFERENCE EXAMPLE 162

To a solution of 0.21 g of (5-methoxy-4-methylpyridin-2-yl)methylacetate in 2 mL of methanol, 0.64 mL of a 20% aqueous sodium hydroxidesolution was added, and the mixture was stirred at room temperature for1 hour. The solvent was distilled off under reduced pressure, water andethyl acetate were added to the resultant residue, the organic layer wasseparated, and the aqueous layer was extracted with ethyl acetate. Theorganic layer and the extract were combined, the resultant solution wasdried over anhydrous magnesium sulfate, and the solvent was distilledoff under reduced pressure to obtain 0.16 g of(5-methoxy-4-methylpyridin-2-yl)methanol as a white solid.

¹H-NMR (CDCl₃) δ: 2.24 (3H, s), 3.92 (3H, s), 4.66 (2H, s), 7.02 (1H,s), 8.09 (1H, s)

REFERENCE EXAMPLE 163

By the same technique as in Reference Example 67,5-methoxy-4-methylpyridine-2-carbaldehyde was obtained from(5-methoxy-4-methylpyridin-2-yl)methanol.

¹H-NMR (CDCl₃) δ: 2.29 (3H, s), 4.03 (3H, s), 7.80 (1H, s), 8.31 (1H,s), 9.96 (1H, s)

REFERENCE EXAMPLE 164

To a solution of 30 mg of (5-(3-thienyl)isoxazol-3-yl)methanol in 5 mLof dichloromethane, 84 mg of Dess-Martin periodinane was added undercooling with ice, and the mixture was stirred at room temperature for 1hour 30 minutes. Thereto was further added 40 mg of Dess-Martinperiodinane, and the mixture was stirred at room temperature for 1 hour30 minutes. Diethyl ether was added to the reaction mixture, theinsoluble substance was filtered off, and the solvent was distilled offunder reduced pressure to obtain 30 mg of5-(3-thienyl)isoxazole-3-carbaldehyde as a yellow solid.

¹H-NMR (CDCl₃) δ: 6.75 (1H, s), 7.42-7.49 (2H, m), 7.88 (1H, dd, J=2.8,1.3 Hz), 10.18 (1H, s)

REFERENCE EXAMPLE 165

To a solution of 0.85 g of2,6-dichloro-3-fluoro-5-((methoxymethoxy)methyl)pyridine in 8 mL ofN,N-dimethylformamide, 0.45 g of lithium chloride was added at roomtemperature, one piece of 2,6-di-tert-butyl-4-methylphenol, 1.04 mL oftributyl(vinyl)tin and 50 mg of bis(triphenylphosphine)palladium (II)dichloride were added at room temperature. Under a nitrogen atmosphere,the mixture was stirred at 40 to 50° C. for 1 hour, and stirred at 50 to60° C. for 1 hour 30 minutes, and then stirred at 70 to 80° C. for 1hour. After cooling to room temperature, the solvent was distilled offunder reduced pressure, and the resultant residue was purified by flashsilica gel column chromatography using an eluent ofchloroform:methanol=9:1 to obtain 0.51 g of a crude product of2-chloro-5-fluoro-3-((methoxymethoxy)methyl)-6-vinylpyridine as aslightly yellow oily substance.

REFERENCE EXAMPLE 166

To a solution of 0.47 g of the crude product of2-chloro-5-fluoro-3-((methoxymethoxy)methyl)-6-vinylpyridine obtained inReference Example 165 in 5 mL of methanol, 0.24 g of 10%palladium-carbon was added, and the mixture was stirred at 40° C. for 1hour under a hydrogen atmosphere. The insoluble substance was filteredoff, the solvent was distilled off under reduced pressure, and theresultant residue was purified by flash silica gel column chromatographyusing an eluent of chloroform:methanol=19:1 to obtain 0.36 g of a crudeproduct of 2-chloro-6-ethyl-5-fluoro-3-((methoxymethoxy)methyl)pyridineas a colorless oily substance.

REFERENCE EXAMPLE 167

To a solution of 0.33 g of the crude product of2-chloro-6-ethyl-5-fluoro-3-((methoxymethoxy)methyl)pyridine obtained inReference Example 166 in 3 mL of N,N-dimethylformamide, 0.16 g oftetrakis(triphenylphosphine)palladium(0) and 0.98 mL of triethylaminewere added at room temperature, and 0.27 mL of formic acid was droppedthereto. The mixture was stirred at 70 to 80° C. for 45 minutes under anitrogen atmosphere. After cooling to room temperature, water and ethylacetate were added to the reaction mixture, the insoluble substance wasfiltered off, the organic layer was separated, and the aqueous layer wasextracted with ethyl acetate. The organic layer and the extract werecombined, the resultant solution was washed with water and a saturatedaqueous sodium chloride solution and dried over anhydrous magnesiumsulfate, and the solvent was distilled off under reduced pressure. Theresultant residue was purified by flash silica gel column chromatographyusing an eluent of chloroform:methanol=9:1 to obtain 0.11 g of2-ethyl-3-fluoro-5-((methoxymethoxy)methyl)pyridine as a colorless oilysubstance.

¹H-NMR (CDCl₃) δ: 1.29 (3H, t, J=7.6 Hz), 2.87 (2H, qd, J=7.6, 2.3 Hz),3.41 (3H, s), 4.59 (2H, s), 4.71 (2H, s), 7.35 (1H, dd, J=10.0, 1.7 Hz),8.31 (1H, s)

REFERENCE EXAMPLE 168

To a solution of 0.11 g of2-ethyl-3-fluoro-5-((methoxymethoxy)methyl)pyridine in 2 mL of1,4-dioxane, 1 mL of 6 mol/L hydrochloric acid was added, and themixture was stirred at 30 to 40° C. for 1 hour. After cooling to roomtemperature, the reaction mixture was charged with water and ethylacetate and adjusted to pH 7.9 with a 20% aqueous sodium hydroxidesolution and a saturated aqueous sodium hydrogen carbonate solution. Theorganic layer was separated, and the aqueous layer was extracted withethyl acetate. The organic layer and the extract were combined, theresultant solution was washed with water and a saturated aqueous sodiumchloride solution and dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure to obtain 87 mg of(6-ethyl-5-fluoropyridin-3-yl)methanol as a light yellow oily substance.

¹H-NMR (CDCl₃) δ: 1.29 (3H, t, J=7.6 Hz), 1.93-2.05 (1H, broad), 2.87(1H, qd, J=7.6, 2.3 Hz), 4.72 (2H, d, J=3.4 Hz), 7.39 (1H, dd, J=10.1,1.6 Hz), 8.30 (1H, s)

REFERENCE EXAMPLE 169

By the same technique as in Reference Example 67,6-ethyl-5-fluoronicotinaldehyde was obtained from(6-ethyl-5-fluoropyridin-3-yl)methanol.

¹H-NMR (CDCl₃) δ: 1.34 (3H, t, J=7.6 Hz), 2.97 (2H, t, J=7.6, 2.4 Hz),7.77 (1H, dd, J=9.0, 1.7 Hz), 8.80 (1H, s), 10.09 (1H, d, J=2.2 Hz)

REFERENCE EXAMPLE 170

To a solution of 2.0 g of5-hydroxy-2-((tetrahydro-2H-pyran-2-yloxy)methyl)-4H-pyran-4-one in 20mL of dichloromethane, 2.1 mL of triethylamine was added, 1.9 mL oftrifluoromethanesulfonic anhydride was dropped under cooling with ice,and the mixture was stirred for 40 minutes. Water and chloroform wereadded to the reaction mixture, the organic layer was separated, and theaqueous layer was extracted with chloroform. The resultant solution wasdried over anhydrous magnesium sulfate, and the solvent was distilledoff under reduced pressure. The resultant residue was purified by silicagel column chromatography using an eluent of hexane:ethyl acetate=2:1 toobtain 2.9 g of4-oxo-6-((tetrahydro-2H-pyran-2-yloxy)methyl)-4H-pyran-3-yltrifluoromethanesulfonate as a light brown solid.

¹H-NMR (CDCl₃) δ: 1.53-1.90 (6H, m), 3.55-3.62 (1H, m), 3.77-3.85 (1H,m), 4.38 (1H, dd, J=14.9, 0.7 Hz), 4.57 (1H, dd, 14.9, 0.7 Hz), 4.74(1H, t, J=3.2 Hz), 6.66 (1H, s), 8.05 (1H, s)

REFERENCE EXAMPLE 171

To a solution of 1.0 g of4-oxo-6-((tetrahydro-2H-pyran-2-yloxy)methyl)-4H-pyran-3-yltrifluoromethanesulfonate in 10 mL of dioxane, 1.2 g of potassiumcarbonate, 0.4 mL of trimethylboroxin and 0.33 g oftetrakis(triphenylphosphine)palladium(0) were added, and the mixture wasstirred at 70 to 80° C. for 2 hours under an argon atmosphere. Aftercooling to room temperature, water and ethyl acetate were added to thereaction mixture, and the organic layer was separated. The aqueous layerwas extracted with ethyl acetate, the organic layer and the extract werecombined, the resultant solution was dried over anhydrous magnesiumsulfate, and the solvent was distilled off under reduced pressure. Theresultant residue was purified by silica gel column chromatography usingan eluent of hexane:ethyl acetate=1:1 to obtain 0.62 g of5-methyl-2-((tetrahydro-2H-pyran-2-yloxy)methyl)-4H-pyran-4-one as abrown oily substance.

¹H-NMR (CDCl₃) δ: 1.20-1.66 (6H, m), 1.66 (3H, s), 3.25-3.35 (1H, m),3.53-3.63 (1H, m), 4.06 (1H, d, J=14.4 Hz), 4.25 (1H, d, J=14.4 Hz),4.47 (1H, t, J=3.3 Hz), 6.16 (1H, s), 7.43 (1H, s)

REFERENCE EXAMPLE 172

To a solution of 0.61 g of5-methyl-2-((tetrahydro-2H-pyran-2-yloxy)methyl)-4H-pyran-4-one in 3 mLof methanol, 0.03 mL of concentrated hydrochloric acid was added, andthe mixture was stirred at room temperature for 1 hour. To the reactionmixture, 0.5 g of potassium carbonate and chloroform were added, and themixture was stirred for 30 minutes. The insoluble substance was filteredoff, the solvent was distilled off under reduced pressure, and theresultant residue was purified by silica gel column chromatography usingan eluent of chloroform:methanol=9:1 to obtain 0.26 g of2-hydroxymethyl-5-methyl-4H-pyran-4-one as a white solid.

¹H-NMR (CDCl₃) δ: 1.92 (3H, d, J=1.1 Hz), 3.03 (1H, t, J=6.7 Hz), 4.47(2H, d, J=6.7 Hz), 6.43 (1H, s), 7.66 (1H, d, J=1.1 Hz)

REFERENCE EXAMPLE 173

By the same technique as in Reference Example 67,5-methyl-4-oxo-4H-pyran-2-carbaldehyde was obtained from2-hydroxymethyl-5-methyl-4H-pyran-4-one.

¹H-NMR (CDCl₃) δ: 1.99 (3H, d, J=1.2 Hz), 6.89 (1H, s), 7.80 (1H, s),9.67 (1H, s)

REFERENCE EXAMPLE 174

To a solution of 1.5 g of methyl 2,6-dichloro-5-fluoronicotinate in 15mL of N,N-dimethylformamide, 0.93 mL of triethylamine was added at roomtemperature, and thereto was dropped 0.56 mL of pyrrolidine. The mixturewas stirred at the same temperature for 1 hour, 56 μL of pyrrolidine wasfurther added, and the mixture was stirred for 50 minutes. After leavingovernight, ethyl acetate and water were added to the reaction mixture.The organic layer was separated, and the aqueous layer was extractedwith ethyl acetate. The organic layer and the extract were combined, theresultant solution was washed with water and a saturated aqueous sodiumchloride solution, and dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure to obtain 1.7 g ofmethyl 2-chloro-5-fluoro-6-(pyrrolidin-1-yl)nicotinate as a white solid.

¹H-NMR (CDCl₃) δ: 1.90-1.99 (4H, m), 3.66-3.74 (4H, m), 3.86 (3H, s),7.73 (1H, dd, J=13.0, 0.6 Hz)

REFERENCE EXAMPLE 175

To a solution of 1.7 g of methyl2-chloro-5-fluoro-6-(pyrrolidin-1-yl)nicotinate in 15 mL ofN,N-dimethylformamide, 0.38 g oftetrakis(triphenylphosphine)palladium(0) and 1.4 mL of triethylaminewere added at room temperature, and 0.37 mL of formic acid was droppedthereto. The mixture was stirred at 80 to 90° C. for 2 hours 30 minutesunder a nitrogen atmosphere. After cooling to room temperature, waterand ethyl acetate were added to the reaction mixture, the organic layerwas separated, and the aqueous layer was extracted with ethyl acetate.The organic layer and the extract were combined, and the resultantsolution was washed with a saturated aqueous sodium chloride solution.To the organic layer, a mixed solvent of chloroform:methanol was added,the organic layer was dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure. To the resultantresidue, a mixed solvent of diethyl ether:ethyl acetate (1:2) was added,the insoluble substance was filtered off, and the solvent was distilledoff under reduced pressure.

The resultant residue was purified by flash silica gel columnchromatography using an eluent of chloroform to obtain 1.3 g of methyl5-fluoro-6-(pyrrolidin-1-yl)nicotinate as a light yellow solid.

¹H-NMR (CDCl₃) δ: 1.95-1.99 (4H, m), 3.69-3.75 (4H, m), 3.86 (3H, s),7.65 (1H, d, J=14.0, 1.8 Hz), 8.56 (1H, t, 1.8 Hz)

REFERENCE EXAMPLE 176

To a solution of 0.24 g of lithium aluminum hydride in 5 mL of THF, asolution of 0.70 g of methyl 5-fluoro-6-(pyrrolidin-1-yl)nicotinate in 5mL of tetrahydrofuran was dropped under cooling with ice. After warmingto room temperature, the mixture was stirred for 45 minutes, thereto wasdropped a saturated aqueous sodium hydrogen carbonate solution undercooling with ice, and the mixture was stirred for 10 minutes. Thereaction mixture was filtered, and the filtration residue was washedwith ethyl acetate and water. The organic layer of the filtrate wasseparated, and the aqueous layer was extracted with ethyl acetate. Theorganic layer and the extract were combined, the resultant solution waswashed with water and a saturated aqueous sodium chloride solution, anddried over anhydrous magnesium sulfate, and the solvent was distilledoff under reduced pressure to obtain 0.68 g of(5-fluoro-6-(pyrrolidin-1-yl)pyridin-3-yl)methanol as a brown oilysubstance.

¹H-NMR (CDCl₃) δ: 1.52-1.57 (1H, m), 1.92-1.98 (4H, m), 3.61-3.66 (4H,m), 4.52-4.56 (2H, m), 7.21 (1H, dd, J=13.9, 1.8 Hz), 7.87 (1H, t, J=1.8Hz)

REFERENCE EXAMPLE 177

By the same technique as in Reference Example 67,5-fluoro-6-(pyrrolidin-1-yl)nicotinaldehyde was obtained from(5-fluoro-6-(pyrrolidin-1-yl)pyridin-3-yl)methanol.

¹H-NMR (CDCl₃) δ: 1.97-2.03 (4H, m), 3.74-3.80 (4H, m), 7.56 (1H, dd,J=13.5, 1.8 Hz), 8.32 (1H, t, J=1.8 Hz), 9.76 (1H, d, J=3.2 Hz)

REFERENCE EXAMPLE 178

By the same technique as in Reference Example 58,(5-(2-furyl)isoxazol-3-yl)methanol was obtained from methyl5-(2-furyl)isoxazole-3-carboxylate.

¹H-NMR (CDCl₃) δ: 1.94-1.99 (1H, m), 4.81 (2H, d, J=6.4 Hz), 6.50 (1H,s), 6.54 (1H, dd, J=3.6, 1.6 Hz), 6.91 (1H, d, J=3.6 Hz), 7.53-7.56 (1H,m)

REFERENCE EXAMPLE 179

By the same technique as in Reference Example 164,5-(2-furyl)isoxazole-3-carbaldehyde was obtained from(5-(2-furyl)isoxazol-3-yl)methanol.

¹H-NMR (CDCl₃) δ: 6.58 (1H, dd, J=3.6, 1.7 Hz), 6.80 (1H, s), 7.01 (1H,d, J=3.6 Hz), 7.60 (1H, d, J=1.7 Hz), 10.18 (1H, s)

REFERENCE EXAMPLE 180

To a solution of 0.11 kg of sodium hydroxide in 1000 mL of water, 1.4 kgof a 12% aqueous sodium hypochlorite solution and 0.40 kg of2-chloro-5-fluoronicotinamide were added, and the mixture was stirred atroom temperature for 2 hours 30 minutes. The reaction mixture was heatedto 45° C. and stirred for 4 hours. The reaction mixture was cooled toroom temperature, and thereto were added ethyl acetate and a 6 mol/Laqueous hydrochloric acid solution. The organic layer was separated, andthe aqueous layer was extracted with ethyl acetate. The organic layerand the extract were combined, anhydrous magnesium sulfate and activecarbon were added thereto, and the mixture was stirred at roomtemperature for 30 minutes. The insoluble substance was filtered off,and the solvent was distilled off under reduced pressure to obtain 0.29kg of 2-chloro-5-fluoropyridin-3-amine as a brown solid.

¹H-NMR (CDCl₃) δ: 4.22 (2H, s), 6.79 (1H, dd, J=9.3, 2.7 Hz), 7.67 (1H,d, J=2.7 Hz)

To a solution of 1.2 g of 2-chloro-5-fluoropyridin-3-amine in 5 mL ofpyridine, 0.86 mL of 2-methylacryloyl chloride was added under coolingwith ice, and the mixture was stirred at room temperature for 30minutes. To the reaction mixture, water and ethyl acetate were added,the organic layer was separated, and the aqueous layer was extractedwith ethyl acetate. The organic layer and the extract were combined, theresultant solution was washed sequentially with water and a saturatedaqueous sodium chloride solution, and dried over anhydrous magnesiumsulfate, and the solvent was distilled off under reduced pressure. Theresultant residue was purified by flash silica gel column chromatographyusing gradient elution with hexane:ethyl acetate=100:0 to 50:50 toobtain 1.1 g of N-(2-chloro-5-fluoropyridin-3-yl)-2-methylacrylamide asa colorless oily substance.

¹H-NMR (CDCl₃) δ: 2.11 (3H, dd, J=1.5, 1.0 Hz), 5.60-5.63 (1H, m),5.93-5.96 (1H, m), 7.99-8.02 (1H, m), 8.15 (1H, s), 8.72 (1H, dd, J=9.9,2.8 Hz)

REFERENCE EXAMPLE 182

To a solution of 1.1 g ofN-(2-chloro-5-fluoropyridin-3-yl)-2-methylacrylamide in 10 mL ofN,N-dimethylformamide, 1.5 mL of triethylamine and 0.13 g ofbis(tri-tert-butylphosphine)palladium(0) were added, and the mixture wasstirred at 110° C. for 3 hours 40 minutes under a nitrogen flow. Theretowas further added 0.13 g of bis(tri-tert-butylphosphine)palladium(0),and the mixture was stirred for 2 hours. Thereto was further added 0.13g of bis(tri-tert-butylphosphine)palladium(0), and the mixture wasstirred for 2 hours. The reaction mixture was cooled to roomtemperature, the solvent was then distilled off under reduced pressure,and diisopropyl ether and ethyl acetate were added to the resultantresidue, the solid was filtered off, and washed with ethyl acetate, tothe solid thus obtained, water, chloroform and methanol were added, theorganic layer was separated and the aqueous layer was extracted withchloroform. The organic layer and the extract were combined, theresultant solution was dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure. To the resultantresidue, diisopropyl ether was added, and the solid was filtered off toobtain 0.25 g of 7-fluoro-4-methyl-1,5-naphthyridin-2(1H)-one as a lightbrown solid.

¹H-NMR (DMSO-d₆) δ: 2.45 (3H, d, J=1.0 Hz), 6.61-6.64 (1H, m), 7.45 (1H,dd, J=9.6, 2.6 Hz), 8.51 (1H, d, J=2.6 Hz), 11.78-11.83 (1H, broad)

REFERENCE EXAMPLE 183

By the same technique as in Reference Example 3,1-(1,3-dioxolan-2-ylmethyl)-7-fluoro-4-methyl-1,5-naphthyridin-2(1H)-onewas obtained from 7-fluoro-4-methyl-1,5-naphthyridin-2(1H)-one and2-bromomethyl-1,3-dioxolan.

¹H-NMR (CDCl₃) δ: 2.54 (3H, d, J=1.2 Hz), 3.82-4.06 (4H, m), 4.43 (2H,d, J=4.1 Hz), 5.18 (1H, t, J=4.1 Hz), 6.75-6.78 (1H, m), 7.67 (1H, dd,J=10.6, 2.4 Hz), 8.41 (1H, d, J=2.4 Hz)

REFERENCE EXAMPLE 184

By the same technique as in Reference Example 4,(7-fluoro-4-methyl-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde wasobtained from1-(1,3-dioxolan-2-ylmethyl)-7-fluoro-4-methyl-1,5-naphthyridin-2(1H)-one.

¹H-NMR (CDCl₃) δ: 2.58 (3H, s), 5.11 (2H, s), 6.80 (1H, s), 7.02 (1H,dd, J=9.6, 2.3 Hz), 8.45 (1H, d, J=2.3 Hz), 9.75 (1H, s)

REFERENCE EXAMPLE 185

To a solution of 0.10 g of (5-bromopyridin-3-yl)methanol in 5 mL ofdioxane, 72 mg of 2-furanboronic acid, 67 mg of lithium chloride, 0.51 gof cesium carbonate, 5.4 mg of palladium acetate and 20 mg of2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl were added at roomtemperature, and the mixture was heated under reflux for 1 hour 30minutes under a nitrogen atmosphere. The reaction mixture was cooled toroom temperature, and the solvent was then distilled off under reducedpressure. The resultant residue was purified by flash silica gel columnchromatography using gradient elution with chloroform:methanol=95:5 to90:10 to obtain 39 mg of (5-(2-furyl)pyridin-3-yl)methanol as a yellowoily substance.

¹H-NMR (CDCl₃) δ: 1.50-1.80 (1H, broad), 4.78 (2H, s), 6.52 (1H, dd,J=3.4, 1.7 Hz), 6.77 (1H, d, J=3.4 Hz), 7.53 (1H, d, J=1.7 Hz), 7.98(1H, s), 8.47 (1H, d, J=1.8 Hz), 8.85 (1H, d, J=1.8 Hz)

REFERENCE EXAMPLE 186

By the same technique as in Reference Example 164,5-(2-furyl)nicotinaldehyde was obtained from(5-(2-furyl)pyridin-3-yl)methanol.

¹H-NMR (CDCl₃) δ: 6.56 (1H, dd, J=3.3, 1.7 Hz), 6.88 (1H, d, J=3.3 Hz),7.58 (1H, d, J=1.7 Hz), 8.39 (1H, t, J=1.9 Hz), 8.95 (1H, d, J=1.9 Hz),9.15 (1H, d, J=1.9 Hz), 10.16 (1H, s)

REFERENCE EXAMPLE 187

To a suspension of 0.50 g of1-(1,3-dioxolan-2-ylmethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one in 3 mLof tetrahydrofuran, 3 mL of a 20% aqueous sodium hydroxide solution wasadded, and the mixture was heated under reflux while stirring for 1hour. Thereto was added 3 mL of water, and the mixture was heated underreflux while stirring for 3 hours 30 minutes. Thereto was added 3 mL ofa 20% aqueous sodium hydroxide solution, and the mixture was heatedunder reflux while stirring for 4 hours. Tetrahydrofuran was distilledoff under reduced pressure, and the mixture was then heated under refluxwhile stirring for 1 hour 30 minutes. After cooling to room temperature,the reaction mixture was added with 2 mol/L hydrochloric acid andadjusted to pH 5. Thereto was added ethyl acetate, the organic layer wasseparated, and the aqueous layer was extracted twice with ethyl acetate.The organic layer and the extract were combined, the resultant solutionwas washed with a saturated aqueous sodium chloride solution and driedover anhydrous magnesium sulfate, and the solvent was distilled offunder reduced pressure. Diethyl ether was added to the resultantresidue, and the solid was filtered off to obtain 0.32 g of1-(1,3-dioxolan-2-ylmethyl)-7-hydroxy-1,5-naphthyridin-2(1H)-one as ayellow solid.

¹H-NMR (DMSO-d₆) δ: 3.76-3.86 (2H, m), 3.92-4.06 (2H, m), 4.32 (2H, d,J=4.6 Hz), 5.08 (1H, t, J=4.6 Hz), 6.61 (1H, d, J=9.6 Hz), 7.37 (1H, d,J=2.2 Hz), 7.84 (1H, d, J=9.6 Hz), 8.14 (1H, d, J=2.2 Hz), 10.6-11.0(1H, broad)

REFERENCE EXAMPLE 188

To a suspension of 0.15 g of1-(1,3-dioxolan-2-ylmethyl)-7-hydroxy-1,5-naphthyridin-2(1H)-one in 1.5mL of toluene, 1 mL of a 40% aqueous sodium hydroxide solution, 97 mg oftetrabutylammonium bromide and 0.25 mL of an N,N-dimethylformamidesolution of 10 mol/L chloro(difluoro)methane were added, the mixture wasstirred for 50 minutes, then, thereto was added 1 mL of anN,N-dimethylformamide solution of 10 mol/L chloro(difluoro)methane, andthe mixture was stirred for 3 hours 40 minutes. Water and toluene wereadded to the reaction mixture, the organic layer was separated, and theaqueous layer was extracted with toluene. The organic layer and theextract were combined, the resultant solution was washed sequentiallywith water and a saturated aqueous sodium chloride solution and driedover anhydrous magnesium sulfate, and the solvent was distilled offunder reduced pressure to obtain 95 mg of7-(difluoromethoxy)-1-(1,3-dioxolan-2-ylmethyl)-1,5-naphthyridin-2(1H)-oneas a light brown solid.

¹H-NMR (CDCl₃) δ: 3.83-4.04 (4H, m), 4.47 (2H, d, J=4.2 Hz), 5.20 (1H,t, J=4.2 Hz), 6.65 (1H, t, J=72.2 Hz), 6.90 (1H, d, J=9.9 Hz), 7.77 (1H,d, J=2.2 Hz), 7.90 (1H, dd, J=9.9, 0.7 Hz), 8.40 (1H, d, J=2.2 Hz)

REFERENCE EXAMPLE 189

By the same technique as in Reference Example 4,(7-(difluoromethoxy)-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde wasobtained from7-(difluoromethoxy)-1-(1,3-dioxolan-2-ylmethyl)-1,5-naphthyridin-2(1H)-one.

¹H-NMR (CDCl₃) δ: 5.13 (2H, s), 6.63 (1H, t, J=71.9 Hz), 6.94 (1H, d,J=9.8 Hz), 7.09 (1H, d, J=2.2 Hz), 7.95-8.00 (1H, m), 8.45 (1H, d, J=2.2Hz), 9.77 (1H, s)

REFERENCE EXAMPLE 190

To a solution of 0.26 g of 3-methyl-1,5-naphthyridine in 4 mL ofbenzene, 0.35 g of N-bromosuccinimide and 29 mg ofazobisisobutyronitrile were added, and the mixture was heated underreflux while stirring for 2 hours 15 minutes. Thereto was further added0.13 g of N-bromosuccinimide, and the mixture was heated under refluxwhile stirring for 30 minutes. After cooling to room temperature, asolution of 0.50 g of hexamethylenetetramine in 1.5 mL of water wasdropped to the reaction mixture under cooling with ice, thereto wasadded 1.5 mL of acetic acid, and the mixture was heated under refluxwhile stirring for 1 hour 20 minutes. After cooling to room temperature,chloroform and a 20% aqueous sodium hydroxide solution were added to thereaction mixture and the mixture was adjusted to pH 8.5. The organiclayer was separated, and the aqueous layer was extracted withchloroform. The organic layer and the extract were combined, theresultant solution was washed with water and a saturated aqueous sodiumchloride solution and dried over anhydrous magnesium sulfate. Thesolvent was distilled off under reduced pressure, and the resultantresidue was purified by flash silica gel column chromatography using aneluent of hexane:ethyl acetate=1:1 to obtain 25 mg of1,5-naphthyridine-3-carbaldehyde as a slightly yellow solid.

¹H-NMR (CDCl₃) δ: 7.80 (1H, dd, 8.5, 4.2 Hz), 8.49-8.52 (1H, m),8.82-8.85 (1H, m), 9.12 (1H, dd, J=4.2, 1.5 Hz), 9.46 (1H, d, J=2.2 Hz),10.35 (1H, s)

REFERENCE EXAMPLE 191

To a solution of 0.10 g of methyl 6-chloropyrazine-2-carboxylate in 2.9mL of dioxane, 65 mg of 2-furanboronic acid, 74 mg of lithium chloride,0.57 g of cesium carbonate, 21 mg of2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl and 24 mg oftris(dibenzylideneacetone)dipalladium(0) were added, and the mixture washeated under reflux for 2 hours. To the reaction mixture, water andethyl acetate were added, the organic layer was separated, washed with asaturated aqueous sodium chloride solution and dried over anhydrousmagnesium sulfate, and the solvent was then distilled off under reducedpressure. The resultant residue was purified by flash silica gel columnchromatography using gradient elution with hexane:ethyl acetate=87:13 to83:17 to obtain 74 mg of methyl 6-(2-furyl)pyrazine-2-carboxylate as awhite solid.

¹H-NMR (CDCl₃) δ: 4.05 (3H, s), 6.60 (1H, dd, J=3.5, 1.8 Hz), 7.30-7.32(1H, m), 7.62-7.65 (1H, m), 9.12 (1H, s), 9.12 (1H, s)

REFERENCE EXAMPLE 192

By the same technique as in Reference Example 58,6-(2-furyl)pyrazin-2-yl)methanol was obtained from methyl6-(2-furyl)pyrazine-2-carboxylate.

¹H-NMR (CDCl₃) δ: 3.08-3.24 (1H, m), 4.86 (2H, s), 6.59 (1H, dd, J=3.4,1.7 Hz), 7.18 (1H, d, J=3.4 Hz), 7.58-7.62 (1H, m), 8.46 (1H, s), 8.89(1H, s)

REFERENCE EXAMPLE 193

By the same technique as in Reference Example 67,6-(2-furyl)pyrazine-2-carbaldehyde was obtained from(6-(2-furyl)pyrazin-2-yl)methanol.

¹H-NMR (CDCl₃) δ: 6.63 (1H, dd, J=3.4, 1.7 Hz), 7.30 (1H, dd, J=3.4, 0.7Hz), 7.66 (1H, dd, J=1.7, 0.7 Hz), 8.99 (1H, s), 9.16 (1H, s), 10.18(1H, s)

REFERENCE EXAMPLE 194

By the same technique as in Reference Example 58,(5-(2-furyl)-1,3-oxazol-2-yl)methanol was obtained from ethyl5-(2-furyl)-1,3-oxazole-2-carboxylate.

¹H-NMR (CDCl₃) δ: 4.78 (2H, s), 6.50 (1H, dd, J=3.4, 2.0 Hz), 6.64 (1H,d, J=3.4 Hz), 7.21 (1H, s), 7.46-7.48 (1H, m)

REFERENCE EXAMPLE 195

By the same technique as in Reference Example 164,5-(2-furyl)-1,3-oxazole-2-carbaldehyde was obtained from(5-(2-furyl)-1,3-oxazol-2-yl)methanol.

¹H-NMR (CDCl₃) δ: 6.57 (1H, dd, J=3.5, 1.8 Hz), 6.94 (1H, d, J=3.5 Hz),7.53 (1H, s), 7.56-7.58 (1H, m), 9.75 (1H, s)

REFERENCE EXAMPLE 196

To a solution of 16 g of4-oxo-6-((tetrahydro-2H-pyran-2-yloxy)methyl)-4H-pyran-3-yltrifluoromethanesulfonate in 100 mL of acetonitrile, 5.1 mL of propargylalcohol, 18 mL of triethylamine, 0.62 g ofdichlorobis(triphenylphosphine)palladium(II) and 0.42 g of copper (I)iodide were added under a nitrogen atmosphere, and the mixture wasstirred at room temperature for 2 hours. The insoluble substance wasfiltered off, and the solvent was distilled off under reduced pressure.The resultant residue was purified by flash silica gel columnchromatography using gradient elution with chloroform:methanol=100:0 to97:3 to obtain 6.2 g of5-(3-hydroxy-1-propyn-1-yl)-2-((tetrahydro-2H-pyran-2-yloxy)methyl)-4H-pyran-4-oneas a brown oily substance.

¹H-NMR (CDCl₃) δ: 1.51-1.90 (6H, m), 2.27-2.40 (1H, broad), 3.52-3.60(1H, m), 3.78-3.86 (1H, m), 4.34 (1H, d, J=14.9 Hz), 4.50 (2H, s), 4.54(1H, d, J=14.9 Hz), 4.73 (1H, t, J=3.3 Hz), 6.51 (1H, s), 8.00 (1H, s)

REFERENCE EXAMPLE 197

By the same technique as in Reference Example 151,5-(3-hydroxypropyl)-2-((tetrahydro-2H-pyran-2-yloxy)methyl)-4H-pyran-4-onewas obtained from5-(3-hydroxy-1-propyn-1-yl)-2-((tetrahydro-2H-pyran-2-yloxy)methyl)-4H-pyran-4-one.

¹H-NMR (CDCl₃) δ: 1.52-1.92 (8H, m), 2.51 (2H, t, J=7.0 Hz), 2.85-3.17(1H, broad), 3.52-3.60 (1H, m), 3.57 (2H, t, J=5.9 Hz), 3.80-3.88 (1H,m), 4.33 (1H, d, J=14.4 Hz), 4.53 (1H, d, J=14.4 Hz), 4.73 (1H, t, J=3.2Hz), 6.46 (1H, s), 7.70 (1H, s)

REFERENCE EXAMPLE 198

To a solution of 1.2 g of5-(3-hydroxypropyl)-2-((tetrahydro-2H-pyran-2-yloxy)methyl)-4H-pyran-4-onein 5 mL of ethanol, 16 mL of 25% ammonium water was added, and themixture was heated under reflux while stirring for 9 hours 30 minutes.The solvent was distilled off under reduced pressure, and the resultantresidue was purified by flash silica gel column chromatography usinggradient elution with chloroform:methanol=95:5 to 90:10 to obtain 0.42 gof5-(3-hydroxypropyl)-2-((tetrahydro-2H-pyran-2-yloxy)methyl)pyridin-4(1H)-oneas a brown oily substance.

¹H-NMR (CDCl₃) δ: 1.52-1.92 (8H, m), 2.64 (2H, t, J=6.5 Hz), 3.51 (2H,t, J=5.6 Hz), 3.55-3.62 (1H, m), 3.93-4.02 (1H, m), 4.55-4.68 (3H, m),6.31 (1H, s), 7.47 (1H, s)

REFERENCE EXAMPLE 199

(1) To a solution of 0.42 g of5-(3-hydroxypropyl)-2-((tetrahydro-2H-pyran-2-yloxy)methyl)pyridin-4(1H)-onein 8 mL of tetrahydrofuran, 0.54 g of triphenylphosphine and 0.89 g of a40% diethyl azodicarboxylate/toluene solution were added, and themixture was stirred for 10 minutes. The solvent was distilled off underreduced pressure to obtain7-((tetrahydro-2H-pyran-2-yloxy)methyl)-3,4-dihydro-2H-pyrano(3,2-c)pyridineas a brown oily substance.

(2) By the same technique as in Reference Example 172,(3,4-dihydro-2H-pyrano(3,2-c)pyridin-7-yl)methanol hydrochloride wasobtained from7-((tetrahydro-2H-pyran-2-yloxy)methyl)-3,4-dihydro-2H-pyrano(3,2-c)pyridine.

¹H-NMR (DMSO-d₆) δ: 1.99 (2H, quint, J=5.8 Hz), 2.84 (2H, t, J=6.2 Hz),4.46 (2H, t, J=5.2 Hz), 4.70 (2H, s), 6.06-6.36 (1H, broad), 7.22 (1H,s), 8.48 (1H, s)

REFERENCE EXAMPLE 200

By the same technique as in Reference Example 123,3,4-dihydro-2H-pyrano(3,2-c)pyridine-7-carbaldehyde was obtained from(3,4-dihydro-2H-pyrano(3,2-c)pyridin-7-yl)methanol hydrochloride.

¹H-NMR (CDCl₃) δ: 2.08 (2H, quint, J=5.8 Hz), 2.85 (2H, t, J=6.4 Hz),4.30 (2H, t, J=5.1 Hz), 7.36 (1H, s), 8.38 (1H, s), 9.97 (1H, s)

REFERENCE EXAMPLE 201

To a solution of 1.8 g of 2-chloro-3-nitro-5-(trifluoromethyl)pyridinein 8 mL of tetrahydrofuran, 2.0 mL of triethyl1,1,2-ethanetricarboxylate and 0.63 g of 60% sodium hydroxide were addedunder cooling with ice, and the mixture was stirred at room temperaturefor 2 hours. Thereto were added water and ethyl acetate, the organiclayer was separated, and washed with a saturated aqueous sodium chloridesolution and dried over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure to obtain 3.5 g of triethyl1-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)ethane-1,1,2-tricarboxylateas a brown oily substance.

¹H-NMR (CDCl₃) δ: 1.20-1.28 (9H, m), 3.57 (2H, s), 4.10 (2H, q, J=7.2Hz), 4.25 (4H, q, J=7.2 Hz), 8.64-8.67 (1H, m), 8.96-8.99 (1H, m)

REFERENCE EXAMPLE 202

(1) To a solution of 3.5 g of triethyl1-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)ethane-1,1,2-tricarboxylatein a mixture of 35 mL of ethanol and 8.8 mL of water, 0.27 g of ammoniumchloride and 1.6 g of iron powder were added, and the mixture was heatedunder reflux while stirring for 2 hours 20 minutes. After cooling toroom temperature, the insoluble substance was filtered off, and washedwith ethyl acetate and water. Thereto was added sodium chloride, theorganic layer was separated, and the aqueous layer was extracted withethyl acetate. The organic layer and the extract were combined, theresultant solution was washed with a saturated aqueous sodium chloridesolution, and dried over anhydrous magnesium sulfate, and the solventwas distilled off under reduced pressure to obtain the residue as abrown oily substance.

(2) To a solution of the residue obtained in (1) in 8 mL of dioxane, 8.0mL of hydrochloric acid was added, and the mixture was heated underreflux while stirring for 1 hour 30 minutes. The solvent was distilledoff under reduced pressure, thereto were added ethanol and diethylether, and the deposit was filtered off to obtain 0.44 g of7-(trifluoromethyl)-3,4-dihydro-1,5-naphthyridin-2(1H)-one hydrochlorideas a light brown solid.

¹H-NMR (DMSO-d₆) δ: 2.65 (2H, t, J=7.7 Hz), 3.13 (2H, t, J=7.7 Hz), 7.46(1H, d, J=1.3 Hz), 8.46 (1H, d, J=1.3 Hz), 10.43 (1H, s)

REFERENCE EXAMPLE 203

By the same technique as in Reference Example 3,1-(2,2-dimethoxyethyl)-7-(trifluoromethyl)-3,4-dihydro-1,5-naphthyridin-2(1H)-onewas obtained from7-(trifluoromethyl)-3,4-dihydro-1,5-naphthyridin-2(1H)-one hydrochlorideand 2-bromo-1,1-dimethoxyethane.

¹H-NMR (CDCl₃) δ: 2.82 (2H, t, J=7.5 Hz), 3.22 (2H, t, J=7.5 Hz),3.43-3.46 (6H, m), 3.99 (2H, d, J=5.1 Hz), 4.61 (1H, t, J=5.1 Hz),7.89-7.92 (1H, m), 8.45-8.48 (1H, m)

REFERENCE EXAMPLE 204

To a solution of 0.11 g of1-(2,2-dimethoxyethyl)-7-(trifluoromethyl)-3,4-dihydro-1,5-naphthyridin-2(1H)-onein 2 mL of dioxane, 0.16 g of 2,3-dichloro-5,6-dicyano-p-benzoquinonewas added, and the mixture was heated under reflux while stirring for 3hours. Thereto were added water and ethyl acetate, the mixture wasadjusted to pH 12 with a 2.0 mol/L aqueous sodium hydroxide solution,and the organic layer was separated. The organic layer was washed withan aqueous sodium hydroxide solution and a saturated aqueous sodiumchloride solution, and dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure to obtain 90 mg of1-(2,2-dimethoxyethyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one asa brown solid.

¹H-NMR (CDCl₃) δ: 3.44 (6H, s), 4.38 (2H, d, J=5.1 Hz), 4.63 (1H, t,J=5.1 Hz), 7.03 (1H, d, J=9.8 Hz), 7.98 (1H, d, J=9.8 Hz), 8.24 (1H, s),8.75 (1H, d, J=1.0 Hz)

REFERENCE EXAMPLE 205

To a solution of 90 mg of1-(2,2-dimethoxyethyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one in0.72 mL of methyl ethyl ketone, 38 μL of concentrated hydrochloric acidwas added, and the mixture was heated under reflux while stirring for 1hour 30 minutes. The reaction mixture was cooled to room temperature,thereto were added chloroform and a saturated aqueous sodium hydrogencarbonate solution, the organic layer was separated, washed with asaturated aqueous sodium chloride solution and dried over anhydrousmagnesium sulfate, and the solvent was distilled off under reducedpressure to obtain 67 mg of(2-oxo-7-(trifluoromethyl)-1,5-naphthyridin-1(2H)-yl)acetaldehyde as abrown oily substance.

¹H-NMR (CDCl₃) δ: 5.21 (2H, s), 7.09 (1H, d, J=9.8 Hz), 7.49 (1H, s),8.04 (1H, d, J=9.8 Hz), 8.79-8.82 (1H, m), 9.82 (1H, s)

REFERENCE EXAMPLE 206

To a suspension of 10 g of 2,6-dichloro-5-fluoronicotinic acid in 30 mLof toluene, 8.5 g of thionyl chloride and 0.10 mL ofN,N-dimethylformamide were added, and the mixture was stirred at 72° C.for 1 hour 30 minutes. The reaction mixture was cooled to roomtemperature, and the solvent was distilled off under reduced pressure.The resultant residue was dropped to 30 mL of 25% ammonium water at −20°C. The temperature was increased to 5 C.°, and the mixture was stirredfor 30 minutes. The solid was filtered off to obtain 9.9 g of2,6-dichloro-5-fluoronicotinamide as a white solid.

¹H-NMR (DMSO-d₆) δ: 7.94 (1H, s), 8.11 (1H, s), 8.23 (1H, d, J=7.8 Hz)

REFERENCE EXAMPLE 207

By the same technique as in Reference Example 101,2-chloro-5-fluoro-6-methylnicotinamide was obtained from2,6-dichloro-5-fluoronicotinamide.

¹H-NMR (CDCl₃) δ: 2.56 (3H, d, J=2.9 Hz), 5.91 (1H, s), 6.85 (1H, s),8.00 (1H, d, J=8.5 Hz)

REFERENCE EXAMPLE 208

By the same technique as in Reference Example 180,2-chloro-5-fluoro-6-methylpyridin-3-amine was obtained from2-chloro-5-fluoro-methylnicotinamide.

¹H-NMR (CDCl₃) δ: 2.37 (3H, d, J=2.7 Hz), 4.04 (2H, s), 6.78 (1H, d,J=9.5 Hz)

REFERENCE EXAMPLE 209

By the same technique as in Reference Example 1, butyl(2E)-3-(3-amino-5-fluoro-6-methylpyridin-2-yl)acrylate was obtained from2-chloro-5-fluoro-6-methylpyridin-3-amine and butyl acrylate.

¹H-NMR (CDCl₃) δ: 0.95 (3H, t, J=7.3 Hz), 1.40-1.48 (2H, m), 1.68 (2H,quint, J=6.8 Hz), 2.40 (3H, d, J=2.7 Hz), 3.93 (2H, s), 4.21 (2H, t,J=6.8 Hz), 6.67 (1H, d, J=10.2 Hz), 6.87 (1H, d, J=15.2 Hz), 7.71 (1H,d, J=15.2 Hz)

REFERENCE EXAMPLE 210

By the same technique as in Reference Example 2,7-fluoro-6-methyl-1,5-naphthyridin-2(1H)-one was obtained from butyl(2E)-3-(3-amino-5-fluoro-6-methylpyridin-2-yl)acrylate.

¹H-NMR (DMSO-d₆) δ: 2.49 (3H, d, J=2.9 Hz), 6.68 (1H, d, J=9.8 Hz), 7.41(1H, J=10.2 Hz), 7.89 (1H, d, J=9.8 Hz), 11.9 (1H, s)

REFERENCE EXAMPLE 211

To a solution of 0.74 g of 7-fluoro-6-methyl-1,5-naphthyridin-2(1H)-onein 5 mL of N,N-dimethylformamide, 2.0 g of cesium carbonate and 0.84 gof 2-bromo-1,1-dimethoxyethane were added, the temperature was increasedto 90 to 100° C., and the mixture was stirred for 2 hours 30 minutes.The reaction mixture was cooled to room temperature, thereto was addedethyl acetate, the insoluble substance was filtered off, and the solventwas then distilled off under reduced pressure. The resultant residue waspurified by silica gel column chromatography using an eluent ofchloroform:methanol=100:1 to obtain 0.69 g of1-(2,2-dimethoxyethyl)-7-fluoro-6-methyl-1,5-naphthyridin-2(1H)-one as alight yellow solid.

¹H-NMR (CDCl₃) δ: 2.58 (3H, d, J=2.7 Hz), 3.43 (6H, s), 4.28 (2H, d,J=5.2 Hz), 4.64 (1H, t, J=5.2 Hz), 6.83 (1H, d, J=9.8 Hz), 7.64 (1H, d,J=11.2 Hz), 7.86 (1H, d, J=9.8 Hz)

REFERENCE EXAMPLE 212

To a solution of 0.69 g of1-(2,2-dimethoxyethyl)-7-fluoro-6-methyl-1,5-naphthyridin-2(1H)-one in 6mL of methyl ethyl ketone, 0.35 mL of concentrated hydrochloric acid wasadded, and the temperature was increased to 74° C., and the mixture wasstirred for 2 hours 50 minutes. The reaction mixture was cooled to roomtemperature, and the solvent was distilled off under reduced pressure.To the resultant residue, ethyl acetate and a saturated aqueous sodiumhydrogen carbonate solution were added, the organic layer was separated,and the aqueous layer was extracted with ethyl acetate. The organiclayer and the extract were combined, the resultant solution was driedover anhydrous magnesium sulfate to obtain 0.52 g of(7-fluoro-6-methyl-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde as alight yellow solid.

¹H-NMR (CDCl₃) δ: 2.59 (3H, d, J=2.7 Hz), 5.10 (2H, s), 6.89 (1H, d,J=10.0 Hz), 7.00 (1H, d, J=10.0 Hz), 7.92 (1H, d, J=9.8 Hz), 9.75 (1H,s)

REFERENCE EXAMPLE 213

To a mixed solution of 0.17 g of tert-butyl(5-(bromomethyl)pyrazin-2-yl)carbamate in 4 mL of dimethyl sulfoxide and2 mL of dichloromethane, 0.26 g of trimethylamine N-oxide dihydrate wasadded under cooling with ice, and the mixture was stirred for 2 hours.Thereto were added water and chloroform, the organic layer wasseparated, and washed with a saturated aqueous sodium hydrogen carbonatesolution, water and a saturated aqueous sodium chloride solution. Theorganic layer was dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure to obtain 0.10 g oftert-butyl (5-formylpyrazin-2-yl)carbamate as a white solid.

¹H-NMR (CDCl₃) δ: 1.55-1.59 (9H, m), 7.63-7.70 (1H, broad), 8.82 (1H, d,J=1.2 Hz), 9.44 (1H, d, J=1.2 Hz), 10.07 (1H, s)

REFERENCE EXAMPLE 214

To a solution of 1.66 g of(7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde in 42 mL ofchloroform, 1.61 g of tert-butyl (piperidin-4-yl)carbamate and 0.48 g ofacetic acid were added, and the mixture was stirred at room temperaturefor 7.5 hours. To the reaction mixture, 2.56 g of sodiumtriacetoxyborohydride was added, and the mixture was stirred for 10hours. Thereto was added a saturated aqueous sodium hydrogen carbonatesolution, and the organic layer was separated. The organic layer waswashed with a saturated aqueous sodium chloride solution and dried overanhydrous magnesium sulfate, and the solvent was distilled off underreduced pressure. Ethanol was added to the resultant residue, and thesolid was filtered off to obtain 0.59 g of tert-butyl(1-(2-(7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamateas a white solid.

¹H-NMR (CDCl₃) δ: 1.31-1.49 (11H, m), 1.84-2.04 (2H, m), 2.14-2.37 (2H,m), 2.56-2.71 (2H, m), 2.82-3.05 (2H, m), 3.35-3.60 (1H, m), 4.20-4.52(3H, m), 6.79-6.93 (1H, m), 7.44-7.58 (1H, m), 7.79-7.96 (1H, m),8.37-8.48 (1H, m)

REFERENCE EXAMPLE 215

A solution of 0.59 g of tert-butyl(1-(2-(7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamatein 30 mL of a 2 mol/L hydrogen chloride/ethanol was stirred at roomtemperature for 18 hours. To the reaction mixture, 2 mL of chloroformwas added, and the mixture was stirred at 40° C. for 4 hours, andstirred at room temperature for 18 hours. In the reaction mixture, thesolvent was distilled off under reduced pressure, the mixture wasneutralized with a saturated aqueous sodium hydrogen carbonate solution,and then the solvent was distilled off under reduced pressure. Theresultant residue was washed with ethanol and, in the mother liquid, thesolvent was distilled off under reduced pressure, and the resultantresidue was purified with silica gel column chromatography using silicagel; Chromatorex-NH made by Fuji Silysia Chemical Ltd. and an eluent ofchloroform:methanol=10:1 to obtain 421 mg of1-(2-(4-aminopiperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-oneas a light yellow solid.

¹H-NMR (CDCl₃) δ: 1.30-1.45 (2H, m), 1.54 (2H, s), 1.75-1.87 (2H, m),2.11-2.24 (2H, m), 2.60-2.76 (3H, m), 2.86-2.99 (2H, m), 4.25-4.39 (2H,m), 6.86 (1H, d, J=9.6 Hz), 7.48-7.60 (1H, m), 7.89 (1H, d, J=9.6 Hz),8.36-8.49 (1H, m)

REFERENCE EXAMPLE 216

To a solution of 1.00 g of 3-bromo-1,5-naphthyridine in 5 mL of1,4-dioxane, 0.67 g of tert-butylcarbamate, 2.18 g of cesium carbonate,44 mg of tris(benzylideneacetone)dipalladium and 83 mg of4,5-bis(diphenylphosphino)-9,9-dimethylxanthene were added, and themixture was stirred at 80° C. for 12.5 hours under an argon atmosphere.Water and chloroform were added to the reaction mixture, and the organiclayer was separated. The organic layer was washed with a saturatedaqueous sodium chloride solution, and dried over anhydrous magnesiumsulfate, and the solvent was distilled off under reduced pressure. Theresultant residue was purified by silica gel column chromatography usingsilica gel; Silica Gel 60N made by KANTO CHEMICAL CO., INC., and aneluent of chloroform:methanol 10:1 to obtain 1.03 g of tert-butyl1,5-naphthyridin-3-ylcarbamate as a yellow oily substance.

¹H-NMR (DMSO-d₆) δ: 1.53 (9H, s), 7.60-7.65 (1H, m), 8.32 (1H, d, J=4.1Hz), 8.52 (1H, s), 8.90-8.93 (1H, m), 8.97-9.00 (1H, m), 10.08 (1H, s)

REFERENCE EXAMPLE 217

To a solution of 1.00 g of tert-butyl 1,5-naphthyridin-3-ylcarbamate in6 mL of methanol, 1 mL of a 12 mol/L aqueous hydrogen chloride solutionwas added, and the mixture was stirred for 30 minutes. To the reactionmixture, 5 mL of methanol and 1 mL of a 12 mol/L aqueous hydrogenchloride solution were added, and the mixture was stirred at 40° C. for40 minutes, and at 80° C. for 40 minutes. In the reaction mixture, thesolvent was distilled off under reduced pressure, the mixture wasneutralized with a saturated aqueous sodium hydrogen carbonate solution,and then the solvent was distilled off under reduced pressure. Theresultant residue was washed with ethanol and, in the mother liquid, thesolvent was distilled off under reduced pressure, and the resultantresidue was purified with silica gel column chromatography using silicagel; Chromatorex-NH made by Fuji Silysia Chemical Ltd., and an eluent ofchloroform:methanol=10:1 to obtain 0.50 g of 1,5-naphthyridin-3-amine asa yellow solid.

¹H-NMR (CDCl₃) δ: 4.18 (2H, s), 7.31-7.42 (1H, m), 7.43-7.50 (1H, m),8.21-8.30 (1H, m), 8.51-8.62 (1H, m), 8.77-8.88 (1H, m)

REFERENCE EXAMPLE 218

To 2 mL of hydrogen fluoride/pyridine, 145 mg of1,5-naphthyridin-3-amine was added at 0° C., 76 mg of sodium nitrite wasadded to the reaction mixture, and stirred at 0° C. for 1 hour. Thereaction mixture was stirred at 60° C. for 1 hour, and neutralized witha saturated aqueous sodium hydrogen carbonate solution at 0° C.,chloroform was then added thereto, and the organic layer was separated.The organic layer was washed with a saturated aqueous sodium chloridesolution, and dried over anhydrous magnesium sulfate, and the solventwas distilled off under reduced pressure. The resultant residue waspurified by silica gel column chromatography using silica gel; SilicaGel 60N made by KANTO CHEMICAL CO., INC., and an eluent ofchloroform:methanol=20:1 to obtain 77 mg of 3-fluoro-1,5-naphthyridineas a light yellow solid.

¹H-NMR (CDCl₃) δ: 7.62-7.67 (1H, m), 8.03-8.08 (1H, m), 8.42-8.47 (1H,m), 8.90-8.94 (1H, m), 8.98-9.03 (1H, m)

REFERENCE EXAMPLE 219

To a solution of 76 mg of 3-fluoro-1,5-naphthyridine in 3 mL ofchloroform, 136 mg of m-chloroperbenzoic acid was added, and the mixturewas stirred at room temperature for 2.5 hours. Thereto was added 27 mgof m-chloroperbenzoic acid, and the mixture was stirred at roomtemperature for 1 hour. To the reaction mixture, a 5% aqueous sodiumthiosulfate solution and chloroform were added, the organic layer wasseparated and dried over anhydrous magnesium sulfate, and the solventwas distilled off under reduced pressure. The resultant residue waspurified by silica gel column chromatography using silica gel; SilicaGel 60N made by KANTO CHEMICAL CO., INC., and an eluent ofchloroform:methanol=50:1 to obtain 60 mg of 7-fluoro-1,5-naphthyridine1-oxide as a light yellow solid.

¹H-NMR (CDCl₃) δ: 7.53 (1H, dd, J=8.7, 6.0 Hz), 8.04 (1H, d, J=8.7 Hz),8.59 (1H, d, J=6.0 Hz), 8.66-8.77 (1H, m), 8.91-9.02 (1H, m)

REFERENCE EXAMPLE 220

To a solution of 60 mg of 7-fluoro-1,5-naphthyridine 1-oxide in 1.6 mLof chloroform, 84 mg of p-toluenesulfonyl chloride, 171 mg of potassiumcarbonate and 0.5 mL of water were added, and the mixture was stirred atroom temperature overnight. The solid was filtered off, and purified bysilica gel column chromatography using silica gel; Chromatorex-NH madeby Fuji Silysia Chemical Ltd., and an eluent of chloroform:methanol=10:1to obtain 14 mg of 7-fluoro-1,5-naphthyridin-2(1H)-one as a white solid.

¹H-NMR (CDCl₃) δ: 6.71 (1H, d, J=10.1 Hz), 7.29-7.57 (1H, m), 7.94 (1H,d, J=10.1 Hz), 8.50 (1H, d, J=2.3 Hz), 12.00 (1H, s)

REFERENCE EXAMPLE 221

To 20.02 g of7-bromo-1-(1,3-dioxolan-2-ylmeythyl)-1,5-naphthyridin-2(1H)-one, 400 mLof an 80% aqueous trifluoroacetic acid solution was added, and themixture was stirred at 90° C. for 3.5 hours. The reaction mixture wascooled to room temperature, and the solvent was then distilled off underreduced pressure. The resultant residue was adjusted to pH 7.7 with a 2mol/L aqueous sodium hydroxide solution. Then, the deposit was filteredoff to obtain 13.43 g of(7-bromo-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde as a brown solid.

¹H-NMR (CDCl₃) δ: 5.13 (2H, s), 6.98 (1H, d, J=9.6 Hz), 7.49 (1H, d,J=1.4 Hz), 7.95 (1H, d, J=9.6 Hz), 8.60 (1H, d, J=1.4 Hz), 9.78 (1H, s)

EXAMPLE 1

To 0.11 g of (7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde,0.15 g of tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(piperidin-4-yl)carbamatein 4 mL of dichloromethane, 24 μL of acetic acid and 0.13 g of sodiumtriacetoxyborohydride were added, and the mixture was stirred at roomtemperature for 1 hour. To the reaction mixture, chloroform and asaturated aqueous sodium hydrogen carbonate solution were added, theorganic layer was separated, and the aqueous layer was extracted withchloroform. The organic layer and the extract were combined, theresultant solution was washed with a saturated aqueous sodium chloridesolution and dried over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure. The resultant residue was purifiedby flash basic silica gel column chromatography using gradient elutionwith hexane:ethyl acetate=100:0 to 20:80, and then gradient eluent ofchloroform:methanol=100:0 to 90:10 to obtain 0.18 g of tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamateas a light yellow foam.

¹H-NMR (CDCl₃) δ: 1.39 (9H, s), 1.40-1.72 (4H, m), 2.06-2.25 (2H, m),2.57-2.64 (2H, m), 2.96-3.05 (2H, m), 3.96 (3H, s), 4.05-4.18 (1H, m),4.23-4.50 (8H, m), 6.73 (1H, d, J=9.8 Hz), 6.73 (1H, s), 7.17 (1H, d,J=2.3 Hz), 7.83 (1H, d, J=9.8 Hz), 8.05 (1H, s), 8.27 (1H, d, J=2.3 Hz)

EXAMPLE 2

To a solution of 0.17 g of tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamatein 3 mL of ethyl acetate, 6.0 mL of a 4.0 mol/L hydrogen chloride/ethylacetate solution was added at room temperature. The mixture was stirredat the same temperature for 1 hour, and the solvent was distilled offunder reduced pressure. Diethyl ether was added to the resultantresidue, and the solid was filtered off to obtain 0.16 g of1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-onehydrochloride as a light yellow solid.

¹H-NMR (D₂O) δ: 1.98-2.13 (2H, m), 2.50-2.60 (2H, m), 3.21-3.34 (2H, m),3.60-3.77 (3H, m), 3.95-4.08 (2H, m), 4.05 (3H, s), 4.42-4.49 (4H, m),4.53-4.59 (2H, m), 4.72-4.87 (2H, m), 6.89 (1H, d, J=9.6 Hz), 7.37 (1H,s), 7.48-7.53 (1H, m), 8.06 (1H, d, J=9.6 Hz), 8.31 (1H, s), 8.40-8.44(1H, m)

EXAMPLE 3

To 0.11 g of (7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde, asolution of 0.19 g of tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl(piperidin-4-yl)carbamatein 3 mL of dichloromethane, 31 μL of acetic acid and 0.17 g of sodiumtriacetoxyborohydride were added, and the mixture was stirred at roomtemperature for 1 hour, and then left overnight. Thereto were addedchloroform and a saturated aqueous sodium hydrogen carbonate solution,the organic layer was separated, and the aqueous layer was extractedwith chloroform. The organic layer and the extract were combined, theresultant solution was washed sequentially with water and a saturatedaqueous sodium chloride solution and dried over anhydrous magnesiumsulfate, and the solvent was distilled off under reduced pressure. Theresultant residue was purified by basic silica gel column chromatographyusing an eluent of chloroform:methanol=19:1 to obtain 0.21 g oftert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamateas a white foam.

¹H-NMR (CDCl₃) δ: 1.39 (9H, s), 1.33-1.71 (4H, m), 2.08-2.24 (2H, m),2.57-2.63 (2H, m), 2.94-3.01 (2H, m), 4.02-4.18 (1H, m), 4.23-4.46 (8H,m), 6.73 (1H, s), 6.84 (1H, d, J=9.8 Hz), 7.47 (1H, dd, J=10.1, 2.4 Hz),7.87 (1H, d, J=9.8 Hz), 8.05 (1H, s), 8.41 (1H, d, J=2.4 Hz)

EXAMPLE 4

To a solution of 0.21 g of tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamatein 4 mL of ethanol, 4 mL of a 6.0 mol/L hydrogen chloride/ethanolsolution was added at room temperature, and the mixture was stirred for1 hour 30 minutes. The solvent was distilled off under reduced pressure,diethyl ether was added to the resultant residue, and the solid wasfiltered off to obtain 0.21 g of1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-onehydrochloride as a light yellow solid.

¹H-NMR (D₂O) δ: 2.00-2.16 (2H, m), 2.52-2.61 (2H, m), 3.23-3.35 (2H, m),3.61-3.67 (2H, m), 3.69-3.80 (1H, m), 3.98-4.07 (2H, m), 4.46-4.51 (2H,m), 4.53 (2H, s), 4.58-4.63 (2H, m), 4.71-4.96 (2H, m), 7.00 (1H, d,J=9.8 Hz), 7.47 (1H, s), 7.93-7.99 (1H, m), 8.10 (1H, d, J=9.8 Hz), 8.37(1H, s), 8.56-8.58 (1H, m)

EXAMPLE 4(2)

To a suspension of 0.30 g of tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamatein 1.8 mL of isopropyl alcohol, 0.23 mL of concentrated hydrochloridewas added, and the mixture was heated under reflux while stirring for 1hour 50 minutes. The reaction mixture was cooled to 5° C., and the solidwas filtered off to obtain 0.28 g of1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-onetrihydrochloride as a light yellow solid.

¹H-NMR (D₂O) δ: 2.00-2.16 (2H, m), 2.52-2.61 (2H, m), 3.23-3.35 (2H, m),3.61-3.67 (2H, m), 3.69-3.80 (1H, m), 3.98-4.07 (2H, m), 4.46-4.51 (2H,m), 4.52 (2H, s), 4.55-4.63 (2H, m), 4.71-4.96 (2H, m), 6.99 (1H, d,J=9.8 Hz), 7.44 (1H, s), 7.93-7.99 (1H, m), 8.10 (1H, d, J=9.8 Hz), 8.36(1H, s), 8.57 (1H, d, J=2.2 Hz)

EXAMPLE 5

By the same technique as in Example 1, tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)-2-methylpiperidin-4-yl)carbamatewas obtained from(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde and tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(2-methylpiperidin-4-yl)carbamate.

¹H-NMR (CDCl₃) δ: 0.99-1.10 (3H, m), 1.33-1.83 (13H, m), 2.57-2.78 (4H,m), 3.14-3.23 (1H, m), 3.96 (3H, s), 4.13-4.53 (9H, m), 6.73 (1H, s),6.73 (1H, d, J=9.6 Hz), 7.19 (1H, d, J=2.2 Hz), 7.83 (1H, d, J=9.6 Hz),8.05 (1H, s), 8.27 (1H, d, J=2.2 Hz)

EXAMPLE 6

By the same technique as in Example2,1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)-2-methylpiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-onewas obtained from tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)-2-methylpiperidin-4-yl)carbamate.

¹H-NMR (CDCl₃) δ: 1.03 (3H, d, J=6.6 Hz), 1.20-1.90 (4H, m), 2.66-2.88(5H, m), 2.95-3.05 (1H, m), 3.77 (2H, d, J=2.7 Hz), 3.97 (3H, s),4.25-4.43 (6H, m), 6.74 (1H, d, J=9.6 Hz), 6.82 (1H, s), 7.20-7.25 (1H,m), 7.84 (1H, d, J=9.6 Hz), 8.10 (1H, s), 8.27 (1H, d, J=2.4 Hz)

To a solution of 53 mg of1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)-2-methylpiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-onein 1 mL of ethyl acetate, 0.23 mL of a 4.0 mol/L hydrogen chloride/ethylacetate solution was added at room temperature, and after stirring, thesolid was filtered off to obtain 40 mg of1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)-2-methylpiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-onehydrochloride as a light yellow solid.

¹H-NMR (DMSO-d₆-D₂O) δ: 1.03 (3H, d, J=6.6 Hz), 2.00-2.35 (4H, m),3.12-3.60 (5H, m), 3.90-4.30 (3H, m), 4.07 (3H, s), 4.33-4.45 (4H, m),4.58-4.86 (2H, m), 6.72 (1H, d, J=9.5 Hz), 7.22 (1H, s), 7.66-7.75 (1H,m), 7.96 (1H, d, J=9.5 Hz), 8.26 (1H, s), 8.34 (1H, d, J=1.9 Hz)

EXAMPLE 7

To a suspension of 0.20 g of1-(2-(4-(aminopiperidin-1-yl)ethyl)-1,7-naphthyridin-2(1H)-onehydrochloride in 3 mL of methanol, 66 mg of sodium cyanoborohydride, 64μL of 3-fluoro-4-methylbenzaldehyde and 0.12 mL of acetic acid wereadded at room temperature, and the mixture was stirred at the sametemperature for 1 hour 30 minutes. Thereto was added 64 μL of3-fluoro-4-methylbenzaldehyde, and the mixture was stirred at the sametemperature for 1 hour 30 minutes. Thereto were further added 33 mg ofsodium cyanoborohydride and 64 μL of 3-fluoro-4-methylbenzaldehyde, andthe mixture was stirred at the same temperature for 3 hours and thenleft overnight. The mixture was charged with chloroform and adjusted topH 9.9 with a saturated aqueous sodium hydrogen carbonate solution and a1 mol/L aqueous sodium hydroxide solution. The organic layer wasseparated, and the aqueous layer was extracted with chloroform. Theorganic layer and the extract were combined, the resultant solution waswashed sequentially with water and a saturated aqueous sodium chloridesolution and dried over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure. The resultant residue was purifiedby basic silica gel column chromatography using an eluent ofchloroform:methanol=10:1 to obtain 0.16 g of1-(2-(4-((3-fluoro-4-methylbenzyl)amino)piperidin-1-yl)ethyl)-1,7-naphthyridin-2(1H)-oneas a slightly yellow oily substance.

¹H-NMR (CDCl₃) δ: 1.37-1.49 (2H, m), 1.87-1.95 (2H, m), 2.17-2.25 (2H,m), 2.26 (3H, d, J=1.7 Hz), 2.48-2.57 (1H, m), 2.68-2.74 (2H, m),2.97-3.04 (2H, m), 3.78 (2H, s), 4.45-4.51 (2H, m), 6.90 (1H, d, J=9.5Hz), 6.97-7.02 (2H, m), 7.10-7.15 (1H, m), 7.43 (1H, d, J=5.1 Hz), 7.66(1H, d, J=9.5 Hz), 8.46 (1H, d, J=5.1 Hz), 8.92 (1H, s)

EXAMPLE 8

To a solution of 0.16 g of1-(2-(4-((3-fluoro-4-methylbenzyl)amino)piperidin-1-yl)ethyl)-1,7-naphthyridin-2(1H)-onein 3 mL of ethyl acetate, 5 mL of a 4.0 mol/L hydrogen chloride/ethylacetate solution was added at room temperature. Thereto was added 2 mLof ethyl acetate, the mixture was stirred at the same temperature for 10minutes, and the solvent was distilled off under reduced pressure. Ethylacetate was added to the resultant residue, and the solid was filteredoff to obtain 0.18 g of1-(2-(4-((3-fluoro-4-methylbenzyl)amino)piperidin-1-yl)ethyl)-1,7-naphthyridin-2(1H)-onehydrochloride as a light yellow solid.

¹H-NMR (D₂O) δ: 1.98-2.11 (2H, m), 2.28 (3H, d, J=1.5 Hz), 2.50-2.58(2H, m), 3.22-3.33 (2H, m), 3.60-3.70 (3H, m), 3.97-4.05 (2H, m), 4.30(2H, s), 4.81-4.87 (2H, m), 7.17-7.22 (2H, m), 7.20 (1H, d, J=9.5 Hz),7.36 (1H, t, J=7.7 Hz), 8.17 (1H, d, J=5.9 Hz), 8.17 (1H, d, J=9.5 Hz),8.61 (1H, d, J=5.9 Hz), 9.12 (1H, s)

EXAMPLE 9

To a solution of 0.16 g of tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(piperidin-4-yl)carbamatein 3 mL of dichloromethane, 0.10 g of(6-methoxy-3-oxopyrido(2,3-b)pyrazin-4(3H)-yl)acetaldehyde, 26 μL ofacetic acid and 0.15 g of sodium triacetoxyborohydride were added, andthe mixture was stirred at room temperature for 30 minutes. To thereaction mixture, chloroform and a saturated aqueous sodium hydrogencarbonate solution were added, the organic layer was separated, and theaqueous layer was extracted with chloroform. The organic layer and theextract were combined, the resultant solution was washed with asaturated aqueous sodium chloride solution and dried over anhydrousmagnesium sulfate, and the solvent was distilled off under reducedpressure. The resultant residue was purified by flash basic silica gelcolumn chromatography using an eluent of chloroform to obtain 0.15 g oftert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(6-methoxy-3-oxopyrido(2,3-b)pyrazin-4(3H)-yl)ethyl)piperidin-4-yl)carbamateas a light brown oily substance.

¹H-NMR (CDCl₃) δ: 1.38 (9H, s), 1.40-1.70 (4H, m), 2.03-2.23 (2H, m),2.66-2.73 (2H, m), 3.02-3.10 (2H, m), 4.00 (3H, s), 4.03-4.20 (1H, m),4.23-4.46 (6H, m), 4.48-4.55 (2H, m), 6.71 (1H, s), 6.72 (1H, d, J=8.5Hz), 8.01 (1H, d, J=8.5 Hz), 8.04 (1H, s), 8.14 (1H, s)

EXAMPLE 10

To a solution of 0.14 g of tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(6-methoxy-3-oxopyrido(2,3-b)pyrazin-4(3H)-yl)ethyl)piperidin-4-yl)carbamatein 3.0 mL of ethanol, 3 mL of a 6.0 mol/L hydrogen chloride/ethanolsolution was added at room temperature. The mixture was stirred at thesame temperature for 3 hours, and the solvent was distilled off underreduced pressure. Diethyl ether was added to the resultant residue, andthe solid was filtered off to obtain 0.11 g of4-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-6-methoxypyrido(2,3-b)pyrazin-3(4H)-onehydrochloride as a light brown solid.

¹H-NMR (D₂O) δ: 1.97-2.12 (2H, m), 2.49-2.58 (2H, m), 3.20-3.34 (2H, m),3.66-3.78 (3H, m), 3.97-4.08 (2H, m), 4.07 (3H, s), 4.44-4.49 (2H, m),4.49 (2H, s), 4.55-4.60 (2H, m), 4.88-4.94 (2H, m), 6.98 (1H, d, J=8.9Hz), 7.41 (1H, s), 8.18 (1H, d, J=8.9 Hz), 8.19 (1H, s), 8.34 (1H, s)

EXAMPLE 11

By the same technique as in Example7,1-(2-(4-((4-ethylbenzyl)amino)piperidin-1-yl)ethyl)-1,7-naphthyridin-2(1H)-onewas obtained from1-(2-(4-aminopiperidin-1-yl)ethyl)-1,7-naphthyridin-2(1H)-onehydrochloride and 4-ethylbenzaldehyde.

¹H-NMR (CDCl₃) δ: 1.23 (3H, t, J=7.6 Hz), 1.37-1.49 (2H, m), 1.87-1.95(2H, m), 2.16-2.24 (2H, m), 2.49-2.58 (1H, m), 2.63 (2H, q, J=7.6 Hz),2.67-2.73 (2H, m), 2.96-3.03 (2H, m), 3.78 (2H, s), 4.44-4.50 (2H, m),6.89 (1H, d, J=9.5 Hz), 7.15 (2H, d, J=8.0 Hz), 7.23 (2H, d, J=8.0 Hz),7.41 (1H, d, J=5.1 Hz), 7.65 (1H, d, J=9.5 Hz), 8.44 (1H, d, J=5.1 Hz),8.91 (1H, s)

EXAMPLE 12

By the same technique as in Example8,1-(2-(4-((4-ethylbenzyl)amino)piperidin-1-yl)ethyl)-1,7-naphthyridin-2(1H)-onehydrochloride was obtained from1-(2-(4-((4-ethylbenzyl)amino)piperidin-1-yl)ethyl)-1,7-naphthyridin-2(1H)-one.

¹H-NMR (D₂O) δ: 1.21 (3H, t, J=7.7 Hz), 1.99-2.12 (2H, m), 2.50-2.59(2H, m), 2.68 (2H, q, J=7.7 Hz), 3.22-3.33 (2H, m), 3.58-3.71 (3H, m),3.97-4.06 (2H, m), 4.30 (2H, s), 4.81-4.87 (2H, m), 7.24 (1H, d, J=9.8Hz), 7.38 (2H, d, J=8.2 Hz), 7.42 (2H, d, J=8.2 Hz), 8.19 (1H, d, J=9.8Hz), 8.24 (1H, d, J=5.9 Hz), 8.63 (1H, d, J=5.9 Hz), 9.16 (1H, s)

EXAMPLE 13

To a solution of 0.75 g of (2-oxo-1,8-naphthyridin-1(2H)-yl)acetaldehydein 40 mL of dichloromethane, 1.4 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate, 0.23mL of acetic acid and 1.3 g of sodium triacetoxyborohydride were added,and the mixture was stirred at room temperature for 2 hours. Theretowere added water, a saturated aqueous sodium hydrogen carbonate solutionand chloroform, the organic layer was separated, and the aqueous layerwas extracted with chloroform. The organic layer and the extract werecombined, the resultant solution was washed with a saturated aqueoussodium chloride solution and dried over anhydrous magnesium sulfate, andthe solvent was distilled off under reduced pressure. The resultantresidue was purified by silica gel column chromatography using an eluentof chloroform:methanol=200:3 to obtain 1.4 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(2-oxo-1,8-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate asa white foam.

¹H-NMR (CDCl₃) δ: 1.41 (9H, s), 1.55-1.70 (4H, m), 2.05-2.25 (2H, m),2.62-2.68 (2H, m), 3.08-3.14 (2H, m), 4.00-4.18 (1H, m), 4.21-4.27 (6H,m), 4.62-4.67 (2H, m), 6.64-6.70 (1H, m), 6.72 (1H, d, J=1.7 Hz), 6.72(1H, d, J=9.5 Hz), 6.77 (1H, d, J=8.3 Hz), 7.15 (1H, dd, J=7.7, 4.7 Hz),7.61 (1H, d, J=9.5 Hz), 7.84 (1H, dd, J=7.7, 1.9 Hz), 8.56 (1H, dd,J=4.7, 1.9 Hz)

EXAMPLE 14

To 1.4 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(2-oxo-1,8-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate,50 mL of a 4 mol/L hydrogen chloride/ethyl acetate solution was added,and the mixture was stirred at room temperature for 1 day. The solventwas distilled off under reduced pressure, thereto was added ethanol, andthe solvent was distilled off under reduced pressure. Ethyl acetate wasadded to the resultant residue, and after stirring, the solid wasfiltered off to obtain 1.2 g of1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-1,8-naphthyridin-2(1H)-onehydrochloride as a white solid.

¹H-NMR (D₂O) δ: 1.93-2.07 (2H, m), 2.48-2.58 (2H, m), 3.18-3.29 (2H, m),3.57-3.78 (3H, m), 4.03-4.10 (2H, m), 4.20-4.27 (2H, m), 4.30-4.40 (4H,m), 4.90-4.95 (2H, m), 6.85 (1H, d, J=9.5 Hz), 6.98-7.06 (3H, m), 7.47(1H, dd, J=7.7, 4.8 Hz), 8.06 (1H, d, J=9.5 Hz), 8.24 (1H, d, J=7.7 Hz),8.70 (1H, d, J=4.8 Hz)

EXAMPLE 15

(1) To 0.60 g of 1-(1,3-dioxolan-2-ylmethyl)-1,6-naphthyridin-2(1H)-one,6 mL of a 90% aqueous trifluoroacetic acid solution was added, and themixture was stirred at room temperature for 12 hours. Thereto was added1.0 mL of water, and the mixture was stirred for 1 hour, and stirred at55 to 75° C. for 3 hours 30 minutes. The solvent was distilled off underreduced pressure, thereto were added a saturated aqueous sodium hydrogencarbonate solution and chloroform, and the mixture was stirred at roomtemperature for 1 hour 30 minutes. The organic layer was then separated,and the aqueous layer was extracted with chloroform. The organic layerand the extract were combined, the resultant solution was dried overanhydrous magnesium sulfate, and the solvent was distilled off underreduced pressure to obtain(2-oxo-1,6-naphthyridin-1(2H)-yl)acetaldehyde.

(2) To a solution of 0.38 g of(2-oxo-1,6-naphthyridin-1(2H)-yl)acetaldehyde in 14 mL ofdichloromethane, 0.35 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate and0.12 mL of acetic acid were added, the mixture was stirred for 5minutes, and then, 0.32 g of sodium triacetoxyborohydride was added tothe reaction mixture and the mixture was stirred for 4 hours 20 minutes.To the reaction mixture, a saturated aqueous sodium hydrogen carbonatesolution and chloroform were added, the organic layer was separated, andthe aqueous layer was extracted with chloroform. The organic layer andthe extract were combined, the resultant solution was washed with asaturated aqueous sodium chloride solution and dried over anhydrousmagnesium sulfate, and the solvent was distilled off under reducedpressure. The resultant residue was purified by silica gel columnchromatography using an eluent of chloroform:methanol=100:1 to obtain0.36 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(2-oxo-1,6-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate asa colorless oily substance.

¹H-NMR (CDCl₃) δ: 1.43 (9H, s), 1.61-1.70 (4H, m), 2.09-2.23 (2H, m),2.58-2.63 (2H, m), 2.98-3.04 (2H, m), 3.95-4.35 (9H, m), 6.64-6.70 (1H,m), 6.73 (1H, d, J=9.5 Hz), 6.74 (1H, d, J=2.4 Hz), 6.78 (1H, d, J=8.3Hz), 7.24 (1H, d, J=5.9 Hz), 7.73 (1H, d, J=9.5 Hz), 8.58 (1H, d, J=5.9Hz), 8.77 (1H, s)

EXAMPLE 16

To 0.15 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(2-oxo-1,6-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate,10 mL of a 4 mol/L hydrogen chloride/ethyl acetate solution was added,and the mixture was stirred at room temperature for 2 hours 30 minutes.Thereto was further added 5 mL of a 4 mol/L hydrogen chloride/ethylacetate solution, the mixture was reacted at room temperature for 20hours, and the solvent was distilled off under reduced pressure. Themixture was dissolved in 8 mL of 6 mol/L hydrochloric acid, and then thesolvent was distilled off under reduced pressure. Ethanol was added tothe resultant residue, and the solvent was distilled off under reducedpressure, and ethyl acetate was then added to the resultant residue, andthe solid was filtered off to obtain 0.13 g of1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-1,6-naphthyridin-2(1H)-onehydrochloride as a light yellow solid.

¹H-NMR (D₂O) δ: 2.02-2.14 (2H, m), 2.52-2.59 (2H, m), 3.27-3.36 (2H, m),3.64-3.70 (3H, m), 3.99-4.07 (2H, m), 4.24-4.26 (2H, m), 4.35 (4H, s),4.80-4.90 (2H, m), 6.98-7.07 (3H, m), 7.08 (1H, d, J=9.8 Hz), 8.06 (1H,d, J=7.3 Hz), 8.25 (1H, d, J=9.8 Hz), 8.79 (1H, d, J=7.1 Hz), 9.23 (1H,s)

EXAMPLE 17

By the same technique as in Example8,1-(2-(4-((3-fluoro-4-methylbenzyl)amino)piperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-onehydrochloride was obtained from1-(2-(4-((3-fluoro-4-methylbenzyl)amino)piperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-one.

¹H-NMR (D₂O) δ: 1.96-2.10 (2H, m), 2.28 (3H, s), 2.48-2.57 (2H, m),3.18-3.31 (2H, m), 3.59-3.68 (3H, m), 3.95-4.06 (2H, m), 4.04 (3H, s),4.29 (2H, s), 4.74-4.83 (2H, m), 6.87 (1H, d, J=9.8 Hz), 7.17-7.22 (2H,m), 7.36 (1H, t, J=7.8 Hz), 7.44 (1H, d, J=2.2 Hz), 8.06 (1H, d, J=9.8Hz), 8.40 (1H, d, J=2.2 Hz)

EXAMPLE 18

To a solution of 0.32 g of (2-oxo-1,7-naphthyridin-1(2H)-yl)acetaldehydein 10 mL of dichloromethane, 0.59 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate and 97μL of acetic acid were added, then, 0.54 g of sodiumtriacetoxyborohydride was added to the reaction mixture, and the mixturewas stirred at room temperature for 2 hours 30 minutes. Thereto wereadded water, a saturated aqueous sodium hydrogen carbonate solution andchloroform, the organic layer was separated, and the aqueous layer wasextracted with chloroform. The organic layer and the extract werecombined, the resultant solution was washed with a saturated aqueoussodium chloride solution and dried over anhydrous magnesium sulfate, andthe solvent was distilled off under reduced pressure. The resultantresidue was purified by silica gel column chromatography using an eluentof chloroform:methanol=100:1 to obtain 0.15 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(2-oxo-1,7-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate asa colorless oily substance.

¹H-NMR (CDCl₃) δ: 1.42 (9H, s), 1.62-1.72 (4H, m), 2.12-2.26 (2H, m),2.63-2.69 (2H, m), 3.00-3.06 (2H, m), 3.98-4.15 (1H, m), 4.22-4.33 (6H,m), 4.41-4.46 (2H, m), 6.67-6.71 (1H, m), 6.74 (1H, d, J=2.0 Hz), 6.78(1H, d, J=8.3 Hz), 6.89 (1H, d, J=9.5 Hz), 7.43 (1H, d, J=5.0 Hz), 7.66(1H, d, J=9.5 Hz), 8.44 (1H, d, J=5.0 Hz), 8.87 (1H, s)

EXAMPLE 19

To 0.15 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(2-oxo-1,7-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 8mL of a 4 mol/L hydrogen chloride/ethyl acetate solution was added, themixture was reacted at room temperature for 21 hours, and the solventwas distilled off under reduced pressure. Ethanol was added to theresultant residue, the solvent was distilled off under reduced pressure,ethyl acetate was then added to the resultant residue, and the solid wasfiltered off to obtain 0.15 g of1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-1,7-naphthyridin-2(1H)-onehydrochloride as a yellow solid.

¹H-NMR (D₂O) δ: 2.01-2.13 (2H, m), 2.52-2.58 (2H, m), 3.26-3.35 (2H, m),3.61-3.72 (3H, m), 4.00-4.07 (2H, m), 4.25 (2H, s), 4.35 (4H, s),4.82-4.89 (2H, m), 6.69-7.07 (3H, m), 7.27 (1H, d, J=9.0 Hz), 8.22 (1H,d, J=9.8 Hz), 8.28 (1H, d, J=5.7 Hz), 8.65 (1H, d, J=5.7 Hz), 9.19 (1H,s)

EXAMPLE 20

To a solution of 0.07 g of1-(2-(4-aminopiperidin-1-yl)ethyl)-1,8-naphthyridin-2(1H)-one in 3 mL ofdichloromethane, 57 mg of7-chloro-3-oxo-3,4-dihydro-2H-pyrido(3,2-b)(1,4)thiazine-6-carbaldehydeand 14 μL of acetic acid were added, the mixture was stirred for 10minutes, and then, 79 mg of sodium triacetoxyborohydride was added tothe reaction mixture, and the mixture was reacted for 1 day. Thereto wasfurther added 7 μL of acetic acid, the mixture was stirred for 35minutes, and then, 7 μL of acetic acid and 26 mg of sodiumtriacetoxyborohydride was added thereto, and the mixture was reacted for20 minutes. To the reaction mixture, water, a saturated aqueous sodiumhydrogen carbonate solution, chloroform and sodium chloride were added,the organic layer was separated, and the aqueous layer was extractedwith chloroform while salting out. The organic layer and the extractwere combined, the resultant solution was dried over anhydrous magnesiumsulfate, and the solvent was distilled off under reduced pressure. Theresultant residue was dissolved in 5 mL of 6 mol/L hydrochloric acid,and the solvent was distilled off under reduced pressure. The resultantresidue was purified by reverse silica gel column chromatography usingan eluent of water to obtain 71 mg of7-chloro-6-(((1-(2-(2-oxo-1,8-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)amino)methyl)-2H-pyrido(3,2-b)(1,4)thiazin-3(4H)-onehydrochloride as a light gray solid.

¹H-NMR (D₂O) δ: 2.03-2.19 (2H, m), 2.56-2.66 (2H, m), 3.22-3.34 (2H, m),3.59-3.85 (5H, m), 4.03-4.15 (2H, m), 4.56 (2H, s), 4.70-5.02 (2H, m),6.83 (1H, d, J=9.4 Hz), 7.44-7.49 (1H, m), 7.93 (1H, s), 8.05 (1H, d,J=9.4 Hz), 8.22 (1H, d, J=7.8 Hz), 8.68-8.73 (1H, m)

EXAMPLE 21

To a solution of 83 mg of1-(2-(4-aminopiperidin-1-yl)ethyl)-1,8-naphthyridin-2(1H)-one in 15 mLof dichloromethane, 54 mg of3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbaldehyde, 86 μL of aceticacid and 0.36 g of sodium triacetoxyborohydride were dividedly addedwhile reacting at room temperature for 1.5 days. To the reactionsolution, water, a saturated aqueous sodium hydrogen carbonate solution,chloroform and sodium chloride were added, the organic layer wasseparated, and the aqueous layer was extracted with chloroform whilesalting out. The organic layer and the extract were combined, theresultant solution was dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure. The resultant residuewas purified by silica gel column chromatography using an eluent ofchloroform:methanol=5:1, and the resultant residue was dissolved in 5 mLof 6 mol/L hydrochloric acid, and then, the solvent was distilled offunder reduced pressure. Diethyl ether was added to the resultantresidue, and the solid was filtered off to obtain 0.12 g of6-(((1-(2-(2-oxo-1,8-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)amino)methyl)-2H-1,4-benzoxazin-3(4H)-onehydrochloride as a light yellow solid.

¹H-NMR (D₂O) δ: 1.94-2.09 (2H, m), 2.50-2.58 (2H, m), 3.18-3.34 (2H, m),3.59-3.70 (3H, m), 3.98-4.11 (2H, m), 4.27 (2H, s), 4.71 (2H, s),4.91-4.97 (2H, m), 6.85 (1H, d, J=9.5 Hz), 7.06-7.11 (2H, m), 7.15 (1H,dd, J=8.4, 1.8 Hz), 7.47 (1H, dd, J=7.8, 4.8 Hz), 8.07 (1H, d, J=9.5Hz), 8.23-8.26 (1H, m), 8.68-8.72 (1H, m)

EXAMPLE 22

To a solution of 0.62 g of (2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehydein 20 mL of dichloromethane, 1.5 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate and0.19 mL of acetic acid were added, and the mixture was stirred at roomtemperature for 30 minutes, and then 1.0 g of sodiumtriacetoxyborohydride was added to the reaction mixture, and the mixturewas stirred at room temperature for 4 days. Thereto were added water, asaturated aqueous sodium hydrogen carbonate solution and chloroform, theorganic layer was separated, and the aqueous layer was extracted withchloroform. The organic layer and the extract were combined, theresultant solution was dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure. The resultant residuewas purified by silica gel column chromatography using an eluent ofchloroform:methanol=75:1 to obtain 0.70 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate asa light brown oily substance.

¹H-NMR (CDCl₃) δ: 1.43 (9H, s), 1.61-1.72 (4H, m), 2.10-2.21 (2H, m),2.61 (2H, t, J=7.3 Hz), 2.97-3.03 (2H, m), 3.97-4.15 (1H, m), 4.20-4.38(8H, m), 6.65-6.76 (2H, m), 6.78 (1H, d, J=8.3 Hz), 6.90 (1H, d, J=9.8Hz), 7.45 (1H, dd, J=8.6, 4.5 Hz), 7.75 (1H, d, J=8.6 Hz), 7.90 (1H, d,J=9.8 Hz), 8.53 (1H, d, J=4.5 Hz)

EXAMPLE 23

To 0.69 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate,25 mL of a 4 mol/L hydrogen chloride/ethyl acetate solution was added,and the mixture was stirred at room temperature for 42 hours. Thesolvent was distilled off under reduced pressure, a mixed solution ofethyl acetate and ethanol (5:1) was added to the resultant residue, andthe solid was filtered off to obtain 0.59 g of1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-1,5-naphthyridin-2(1H)-onehydrochloride as a light yellow solid.

¹H-NMR (D₂O) δ: 1.98-2.12 (2H, m), 2.46-2.58 (2H, m), 3.21-3.36 (2H, m),3.56-3.70 (3H, m), 3.97-4.07 (2H, m), 4.20-4.25 (2H, m), 4.33 (4H, s),4.80-5.60 (2H, m), 6.96-7.05 (3H, m), 7.24 (1H, d, J=10.0 Hz), 8.09 (1H,dd, J=8.9, 5.2 Hz), 8.22 (1H, d, J=10.0 Hz), 8.54 (1H, d, J=8.9 Hz),8.77 (1H, d, J=5.2 Hz)

EXAMPLE 24

By the same technique as in Example7,1-(2-(4-((2-naphthylmethyl)amino)piperidin-1-yl)ethyl)-1,7-naphthyridin-2(1H)-onewas obtained from1-(2-(4-aminopiperidin-1-yl)ethyl)-1,7-naphthyridin-2(1H)-onehydrochloride and 2-naphthaldehyde.

¹H-NMR (CDCl₃) δ: 1.41-1.51 (2H, m), 1.91-1.99 (2H, m), 2.16-2.25 (2H,m), 2.54-2.62 (1H, m), 2.68-2.73 (2H, m), 2.98-3.04 (2H, m), 3.99 (2H,s), 4.45-4.50 (2H, m), 6.89 (1H, d, J=9.5 Hz), 7.42 (1H, d, J=5.0 Hz),7.43-7.48 (3H, m), 7.65 (1H, d, J=9.5 Hz), 7.76 (1H, s), 7.79-7.84 (3H,m), 8.44 (1H, d, J=5.0 Hz), 8.91 (1H, s)

EXAMPLE 25

By the same technique as in Example8,1-(2-(4-((2-naphthylmethyl)amino)piperidin-1-yl)ethyl)-1,7-naphthyridin-2(1H)-onehydrochloride was obtained from1-(2-(4-((2-naphthylmethyl)amino)piperidin-1-yl)ethyl)-1,7-naphthyridin-2(1H)-one.

¹H-NMR (DMSO-d₆) δ: 2.08-2.22 (2H, m), 2.40-2.48 (2H, m), 3.08-3.20 (2H,m), 3.28-3.87 (5H, m), 4.34-4.43 (2H, m), 4.70-4.79 (2H, m), 7.01 (1H,d, J=9.5 Hz), 7.56-7.63 (2H, m), 7.78 (1H, d, J=8.3 Hz), 7.90-8.04 (4H,m), 8.09 (1H, d, J=9.5 Hz), 8.14 (1H, s), 8.55 (1H, d, J=5.4 Hz), 9.26(1H, s), 9.78-9.97 (2H, m), 10.82-10.96 (1H, m)

EXAMPLE 26

To a suspension of 0.20 g of1-(2-(4-aminopiperidin-1-yl)ethyl)-1,7-naphthyridin-2(1H)-onehydrochloride in 6 mL of methanol, 99 mg of sodium cyanoborohydride and0.40 g of molecular sieves 3 A were added, and the mixture was stirredat room temperature for 15 minutes. Thereto was added 68 mg ofphenylpropargyl aldehyde, and the mixture was stirred at roomtemperature for 1 hour 30 minutes. Thereto was added 68 mg ofphenylpropargyl aldehyde, and the mixture was stirred at roomtemperature for 2 hours. Thereto was added 68 mg of phenylpropargylaldehyde, and the mixture was stirred at room temperature for 1 hour 30minutes. A saturated aqueous sodium hydrogen carbonate solution andchloroform were added thereto, and the insoluble substance was filteredoff. The organic layer was separated, washed sequentially with water anda saturated aqueous sodium chloride solution, and dried over anhydrousmagnesium sulfate, and the solvent was distilled off under reducedpressure. The resultant residue was purified by basic silica gel columnchromatography using an eluent of chloroform:methanol=50:1 to obtain0.11 g of1-(2-(4-(bis(3-phenyl-2-propynyl)amino)piperidin-1-yl)ethyl)-1,7-naphthyridin-2(1H)-oneas a light yellow oily substance.

¹H-NMR (CDCl₃) δ: 1.59-1.72 (2H, m), 1.99-2.07 (2H, m), 2.18-2.26 (2H,m), 2.66-2.75 (3H, m), 3.06-3.14 (2H, m), 3.84 (4H, s), 4.45-4.52 (2H,m), 6.89 (1H, d, J=9.5 Hz), 7.27-7.46 (11H, m), 7.65 (1H, d, J=9.8 Hz),8.44 (1H, d, J=5.1 Hz), 8.91 (1H, s)

EXAMPLE 27

By the same technique as in Example8,1-(2-(4-(bis(3-phenyl-2-propynyl)amino)piperidin-1-yl)ethyl)-1,7-naphthyridin-2(1H)-onehydrochloride was obtained from1-(2-(4-(bis(3-phenyl-2-propynyl)amino)piperidin-1-yl)ethyl)-1,7-naphthyridin-2(1H)-one.

¹H-NMR (DMSO-d₆) δ: 2.10-2.25 (2H, m), 2.38-2.50 (2H, m), 3.18-3.30 (2H,m), 3.38-3.92 (5H, m), 4.32-4.42 (4H, m), 4.71-4.79 (2H, m), 7.04 (1H,d, J=9.5 Hz), 7.34-7.54 (10H, m), 7.98 (1H, d, J=5.4 Hz), 8.11 (1H, d,J=9.5 Hz), 8.58 (1H, d, J=5.4 Hz), 9.31 (1H, s)

EXAMPLE 28

By the same technique as in Example7,1-(2-(4-((1-benzothiophen-2-ylmethyl)amino)piperidin-1-yl)ethyl)-1,7-naphthyridin-2(1H)-onewas obtained from1-(2-(4-aminopiperidin-1-yl)ethyl)-1,7-naphthyridin-2(1H)-onehydrochloride and 1-benzothiophene-2-carbaldehyde.

¹H-NMR (CDCl₃) δ: 1.39-1.50 (2H, m), 1.89-1.97 (2H, m), 2.15-2.24 (2H,m), 2.57-2.66 (1H, m), 2.68-2.73 (2H, m), 2.97-3.04 (2H, m), 4.11 (2H,d, J=0.8 Hz), 4.44-4.50 (2H, m), 6.89 (1H, d, J=9.5 Hz), 7.14 (1H, s),7.27-7.34 (2H, m), 7.42 (1H, d, J=5.1 Hz), 7.65 (1H, d, J=9.5 Hz),7.67-7.72 (1H, m), 7.79 (1H, d, J=7.6 Hz), 8.44 (1H, d, J=5.1 Hz), 8.90(1H, s)

EXAMPLE 29

By the same technique as in Example8,1-(2-(4-((1-benzothiophen-2-ylmethyl)amino)piperidin-1-yl)ethyl)-1,7-naphthyridin-2(1H)-onehydrochloride was obtained from1-(2-(4-((1-benzothiophen-2-ylmethyl)amino)piperidin-1-yl)ethyl)-1,7-naphthyridin-2(1H)-one.

¹H-NMR (DMSO-d₆) δ: 2.02-2.16 (2H, m), 2.38-2.46 (2H, m), 3.11-3.22 (2H,m), 3.35-3.46 (3H, m), 3.79-3.88 (2H, m), 4.58 (2H, s), 4.69-4.78 (2H,m), 7.06 (1H, d, J=9.6 Hz), 7.40-7.46 (2H, m), 7.72 (1H, s), 7.88-7.94(1H, m), 8.00-8.05 (2H, m), 8.13 (1H, d, J=9.6 Hz), 8.59 (1H, d, J=5.4Hz), 9.31 (1H, s)

EXAMPLE 30

To a suspension of 0.10 g of1-(2-(4-aminopiperidin-1-yl)ethyl)-1,7-naphthyridin-2(1H)-onehydrochloride in 3 mL of methanol, 0.15 mL of a 28% sodiummethoxide/methanol solution and 15 μL of acetic acid were added. Theretowere added 51 mg of7-chloro-3-oxo-3,4-dihydro-2H-pyrido(3,2-b)(1,4)thiazine-6-carbaldehydeand 0.20 g of molecular sieves 3 A, and the mixture was stirred at roomtemperature for 30 minutes. Thereto was added 33 mg of sodiumcyanoborohydride, and the mixture was stirred at room temperature for 1hour 30 minutes. Thereto was added 51 mg of7-chloro-3-oxo-3,4-dihydro-2H-pyrido(3,2-b)(1,4)thiazine-6-carbaldehyde,and the mixture was stirred at room temperature for 2 hours. Theinsoluble substance was filtered off, and chloroform and a saturatedaqueous sodium hydrogen carbonate solution were added thereto. Theorganic layer was separated, and washed sequentially with water and asaturated aqueous sodium chloride solution. The organic layer was driedover anhydrous magnesium sulfate, and the solvent was distilled offunder reduced pressure. The resultant residue was purified by basicsilica gel column chromatography using an eluent of chloroform:methanol10:1 to obtain 97 mg of7-chloro-6-(((1-(2-(2-oxo-1,7-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)amino)methyl)-2H-pyrido(3,2-b)(1,4)thiazin-3(4H)-oneas a white solid.

¹H-NMR (CDCl₃) δ: 1.43-1.60 (2H, m), 1.88-1.96 (2H, m), 2.18-2.26 (2H,m), 2.50-2.58 (1H, m), 2.69-2.76 (2H, m), 2.97-3.05 (2H, m), 3.48 (2H,s), 3.95 (2H, s), 4.44-4.50 (2H, m), 6.90 (1H, d, J=9.5 Hz), 7.42 (1H,d, J=4.9 Hz), 7.60 (1H, s), 7.65 (1H, d, J=9.5 Hz), 8.17 (1H, s), 8.45(1H, d, J=4.9 Hz), 8.92 (1H, s)

EXAMPLE 31

By the same technique as in Example 30,1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-1,7-naphthyridin-2(1H)-onewas obtained from1-(2-(4-aminopiperidin-1-yl)ethyl)-1,7-naphthyridin-2(1H)-onehydrochloride and 2,3-dihydro(1,4)dioxino(2,3-c)pyridine-7-carbaldehyde.

¹H-NMR (CDCl₃) δ: 1.40-1.52 (2H, m), 1.87-1.95 (2H, m), 2.16-2.25 (2H,m), 2.49-2.57 (1H, m), 2.67-2.74 (2H, m), 2.97-3.04 (2H, m), 3.80 (2H,s), 4.26-4.36 (4H, m), 4.44-4.51 (2H, m), 6.83 (1H, s), 6.89 (1H, d,J=9.5 Hz), 7.42 (1H, d, J=5.1 Hz), 7.65 (1H, d, J=9.5 Hz), 8.11 (1H, s),8.45 (1H, d, J=5.1 Hz), 8.91 (1H, s)

EXAMPLE 32

By the same technique as in Example8,1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-1,7-naphthyridin-2(1H)-onehydrochloride was obtained from1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-1,7-naphthyridin-2(1H)-one.

¹H-NMR (D₂O) δ: 1.98-2.11 (2H, m), 2.49-2.57 (2H, m), 3.23-3.33 (2H, m),3.62-3.72 (3H, m), 3.96-4.05 (2H, m), 4.38 (2H, s), 4.39-4.44 (2H, m),4.46-4.51 (2H, m), 4.80-4.86 (2H, m), 7.19 (1H, d, J=9.5 Hz), 7.22 (1H,s), 8.15 (1H, d, J=5.7 Hz), 8.17 (1H, d, J=9.5 Hz), 8.23 (1H, s), 8.60(1H, d, J=5.7 Hz), 9.10 (1H, s)

EXAMPLE 33

By the same technique as in Example 30,6-(1-(2-(2-oxo-1,7-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)amino)methyl)-2H-pyrido(3,2-b)(1,4)thiazin-3(4H)-onewas obtained from1-(2-(4-aminopiperidin-1-yl)ethyl)-1,7-naphthyridin-2(1H)-onehydrochloride and3-oxo-3,4-dihydro-2H-pyrido(3,2-b)(1,4)thiazine-6-carbaldehyde.

¹H-NMR (CDCl₃) δ: 1.39-1.51 (2H, m), 1.86-1.95 (2H, m), 2.16-2.25 (2H,m), 2.47-2.57 (1H, m), 2.68-2.74 (2H, m), 2.97-3.04 (2H, m), 3.48 (2H,s), 3.83 (2H, s), 4.44-4.50 (2H, m), 6.89 (1H, d, J=9.4 Hz), 6.98 (1H,d, J=7.8 Hz), 7.42 (1H, d, J=5.1 Hz), 7.57 (1H, d, J=7.8 Hz), 7.65 (1H,d, J=9.4 Hz), 8.02-8.10 (1H, broad), 8.45 (1H, d, J=5.1 Hz), 8.91 (1H,s)

EXAMPLE 34

By the same technique as in Example 30,1-(2-(4-(((5-(2-thienyl)isoxazol-3-yl)methyl)amino)piperidin-1-yl)ethyl)-1,7-naphthyridin-2(1H)-onewas obtained from1-(2-(4-aminopiperidin-1-yl)ethyl)-1,7-naphthyridin-2(1H)-onehydrochloride and 5-(2-thienyl)isoxazole-3-carbaldehyde.

¹H-NMR (CDCl₃) δ: 1.38-1.49 (2H, m), 1.88-1.96 (2H, m), 2.17-2.26 (2H,m), 2.52-2.62 (1H, m), 2.68-2.74 (2H, m), 2.97-3.04 (2H, m), 3.91 (2H,s), 4.44-4.50 (2H, m), 6.40 (1H, s), 6.89 (1H, d, J=9.5 Hz), 7.12 (1H,dd, J=5.1, 3.7 Hz), 7.40-7.46 (2H, m), 7.50 (1H, dd, J=3.7, 1.0 Hz),7.65 (1H, d, J=9.5 Hz), 8.44 (1H, d, J=5.1 Hz), 8.90 (1H, s)

EXAMPLE 35

By the same technique as in Example 8,1-(2-(4-(((5-(2-thienyl)isoxazol-3-yl)methyl)amino)piperidin-1-yl)ethyl)-1,7-naphthyridin-2(1H)-onehydrochloride was obtained from1-(2-(4-(((5-(2-thienyl)isoxazol-3-yl)methyl)amino)piperidin-1-yl)ethyl)-1,7-naphthyridin-2(1H)-one.

¹H-NMR (DMSO-d₆) δ: 2.05-2.18 (2H, m), 2.36-2.46 (2H, m), 3.10-3.22 (2H,m), 3.35-3.40 (3H, m), 3.60-3.88 (2H, m), 4.38-4.46 (2H, m), 4.70-4.79(2H, m), 7.02 (1H, d, J=9.5 Hz), 7.15 (1H, s), 7.28 (1H, dd, J=5.1, 3.7Hz), 7.74 (1H, d, J=3.7 Hz), 7.89 (1H, d, J=5.1 Hz), 7.94 (1H, d, J=5.1Hz), 8.10 (1H, d, J=9.5 Hz), 8.56 (1H, d, J=5.1 Hz), 9.27 (1H, s),10.20-10.40 (2H, broad), 10.73-10.90 (1H, broad)

EXAMPLE 36

By the same technique as in Example 30,1-(2-(4-((3-phenyl-2-propynyl)amino)piperidin-1-yl)ethyl)-1,7-naphthyridin-2(1H)-onewas obtained from1-(2-(4-aminopiperidin-1-yl)ethyl)-1,7-naphthyridin-2(1H)-onehydrochloride and phenylpropargyl aldehyde.

¹H-NMR (CDCl₃) δ: 1.40-1.52 (2H, m), 1.88-1.96 (2H, m), 2.22-2.33 (2H,m), 2.70-2.85 (3H, m), 2.99-3.07 (2H, m), 3.68 (2H, s), 4.46-4.52 (2H,m), 6.89 (1H, d, J=9.5 Hz), 7.28-7.32 (3H, m), 7.38-7.44 (3H, m), 7.65(1H, d, J=9.5 Hz), 8.44 (1H, d, J=5.1 Hz), 8.92 (1H, s)

EXAMPLE 37

By the same technique as in Example8,1-(2-(4-((3-phenyl-2-propynyl)amino)piperidin-1-yl)ethyl)-1,7-naphthyridin-2(1H)-onehydrochloride was obtained from1-(2-(4-((3-phenyl-2-propynyl)amino)piperidin-1-yl)ethyl)-1,7-naphthyridin-2(1H)-one.

¹H-NMR (DMSO-d₆) δ: 2.00-2.13 (2H, m), 2.32-2.41 (2H, m), 3.14-3.26 (2H,m), 3.35-3.75 (3H, m), 3.80-3.86 (2H, m), 4.20-4.28 (2H, m), 4.70-4.78(2H, m), 7.01 (1H, d, J=9.5 Hz), 7.42-7.48 (3H, m), 7.51-7.56 (2H, m),7.92 (1H, d, J=5.4 Hz), 8.09 (1H, d, J=9.5 Hz), 8.56 (1H, d, J=5.1 Hz),9.26 (1H, s), 9.99-10.08 (2H, m), 10.70-10.82 (1H, m)

EXAMPLE 38

By the same technique as in Example 30,6-(((1-(2-(2-oxo-1,7-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)amino)methyl)-2H-1,4-benzoxazin-3(4H)-onewas obtained from1-(2-(4-aminopiperidin-1-yl)ethyl)-1,7-naphthyridin-2(1H)-onehydrochloride and 3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbaldehyde.

¹H-NMR (DMSO-d₆) δ: 1.13-1.25 (2H, m), 1.70-1.79 (2H, m), 1.97-2.06 (2H,m), 2.28-2.37 (1H, m), 2.46-2.57 (2H, m), 2.84-2.92 (2H, m), 3.59 (2H,s), 4.35-4.42 (2H, m), 4.50 (2H, s), 6.81-6.90 (4H, m), 7.67 (1H, d,J=5.0 Hz), 7.94 (1H, d, J=9.5 Hz), 8.40 (1H, d, J=5.0 Hz), 8.92 (1H, s),10.61 (1H, s)

EXAMPLE 39

(1) By the same technique as in Example 1, tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)-2-methylpiperidin-4-yl)carbamatewas obtained from(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde and tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(2-methylpiperidin-4-yl)carbamate.

(2) By the same technique as in Example 54,1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)-2-methylpiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-onewas obtained from tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)-2-methylpiperidin-4-yl)carbamate.

¹H-NMR (CDCl₃) δ: 1.11 (3H, d, J=6.1 Hz), 1.22-1.44 (2H, m), 1.84-1.98(2H, m), 2.28-2.44 (1H, m), 2.56-2.61 (2H, m), 2.68-2.90 (1H, m),2.97-3.07 (1H, m), 3.08-3.16 (1H, m), 3.79 (2H, s), 3.97 (3H, s),4.16-4.20 (1H, m), 4.34-4.38 (4H, m), 4.55-4.59 (1H, m), 6.74 (1H, d,J=9.6 Hz), 6.81 (1H, s), 7.24 (1H, d, J=2.3 Hz), 7.84 (1H, d, J=9.6 Hz),8.10 (1H, s), 8.27 (1H, d, J=2.3 Hz)

EXAMPLE 40

To a solution of 0.13 g of1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-onehydrochloride in 2.6 mL of N,N-dimethylformamide, 75 mg of5,6,7,8-tetrahydroquinoxaline-2-carbaldehyde, 0.26 mL of acetic acid,0.21 mL of triethylamine and 98 mg of sodium triacetoxyborohydride wereadded, and the mixture was stirred at room temperature for 9 hours 40minutes. Thereto were added water, a saturated aqueous sodium hydrogencarbonate solution, and ethyl acetate, and the reaction mixture wasadjusted to pH 11.5 with a 20% aqueous sodium hydroxide solution, theorganic layer was then separated, and the aqueous layer was extractedwith ethyl acetate. The organic layer and the extract were combined, theresultant solution was washed with a saturated aqueous sodium chloridesolution and dried over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure. The resultant residue was purifiedby basic silica gel column chromatography using an eluent ofchloroform:methanol=10:1, and thereto were added ethyl acetate and a 4mol/L hydrogen chloride/ethyl acetate solution. The solvent wasdistilled off under reduced pressure, diethyl ether was added thereto,and the solid was filtered off to obtain 92 mg of7-methoxy-1-(2-(4-((5,6,7,8-tetrahydroquinoxalin-2-ylmethyl)amino)piperidin-1-yl)ethyl)-1,5-naphthyridin-2(1H)-onehydrochloride as a light brown solid.

¹H-NMR (D₂O) δ: 1.87-1.95 (4H, m), 2.01-2.14 (2H, m), 2.51-2.60 (2H, m),2.92-3.00 (4H, m), 3.19-3.34 (2H, m), 3.59-3.78 (3H, m), 3.97-4.06 (2H,m), 4.04 (3H, s), 4.47 (2H, s), 4.76-4.79 (2H, m), 6.88 (1H, d, J=9.8Hz), 7.47 (1H, d, J=2.1 Hz), 8.06 (1H, d, J=9.8 Hz), 8.39 (1H, s), 8.41(1H, d, J=2.1 Hz)

EXAMPLE 41

(1) To 95 mg of1-(1,3-dioxolan-2-ylmethyl)pyrido(3,4-b)pyrazin-2(1H)-one, 4.0 mL of an80% aqueous trifluoroacetic acid solution was added, and the mixture wasstirred at room temperature for 2 hours, and then left overnight.Thereto was added 4.0 mL of an 80% aqueous trifluoroacetic acidsolution, and the mixture was stirred at 50 to 70° C. for 6 hours. Thereaction mixture was cooled to room temperature, and the solvent wasdistilled off under reduced pressure. The resultant residue was chargedwith chloroform and water and adjusted to pH 7.0 with a 1 mol/L aqueoussodium hydroxide solution. The organic layer was separated, and theaqueous layer was extracted with chloroform. The organic layer and theextract were combined, the resultant solution was dried over anhydrousmagnesium sulfate, and the solvent was distilled off under reducedpressure to obtain 40 mg of(2-oxopyrido(3,4-b)pyrazin-1(2H)-yl)acetaldehyde as a light brown oilysubstance.

(2) To a suspension of 40 mg of(2-oxopyrido(3,4-b)pyrazin-1(2H)-yl)acetaldehyde in 2 mL ofdichloromethane, a solution of 74 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl) carbamate in 2mL of dichloromethane, and 12 μL of acetic acid were added, and themixture was stirred at room temperature for 10 minutes. Thereto wasadded 67 mg of sodium triacetoxyborohydride, and the mixture was stirredat room temperature for 30 minutes. To the reaction mixture, chloroformand a saturated aqueous sodium hydrogen carbonate solution were added,the organic layer was separated, and the aqueous layer was extractedwith chloroform. The organic layer and the extract were combined, theresultant solution was washed with a saturated aqueous sodium chloridesolution and dried over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure. The resultant residue was purifiedby flash silica gel column chromatography using gradient elution withchloroform:methanol=100:0 to 90:10 to obtain 80 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl(1-(2-(2-oxopyrido(3,4-b)pyrazin-1(2H)-yl)ethyl)piperidin-4-yl)carbamateas a light brown oily substance.

¹H-NMR (CDCl₃) δ: 1.42 (9H, s), 1.54-1.72 (4H, m), 2.05-2.23 (2H, m),2.59-2.66 (2H, m), 2.91-3.00 (2H, m), 3.95-4.14 (1H, m), 4.20-4.30 (8H,m), 6.64-6.70 (1H, m), 6.73 (1H, d, J=2.0 Hz), 6.78 (1H, d, J=8.3 Hz),7.23 (1H, d, J=5.9 Hz), 8.30 (1H, s), 8.61 (1H, d, J=5.9 Hz), 9.08 (1H,s)

EXAMPLE 42

By the same technique as in Example2,1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)pyrido(3,4-b)pyrazin-2(1H)-onehydrochloride was obtained from tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(2-oxopyrido(3,4-b)pyrazin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate.

¹H-NMR (D₂O) δ: 1.83-1.98 (2H, m), 2.34-2.45 (2H, m), 3.09-3.21 (2H, m),3.40-3.56 (3H, m), 3.82-3.90 (2H, m), 4.10 (2H, s), 4.21 (4H, s),4.50-4.80 (2H, m), 6.85-6.92 (3H, m), 7.86 (1H, d, J=6.8 Hz), 8.40 (1H,s), 8.69 (1H, d, J=6.8 Hz), 9.16 (1H, s)

EXAMPLE 43

To a solution of 0.20 g of(7-methoxy-2-oxo-1,8-naphthyridin-1(2H)-yl)acetaldehyde in 20 mL ofdichloromethane, 0.32 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate and 53μL of acetic acid were added, and the mixture was stirred at roomtemperature for 15 minutes. To the reaction mixture, 0.29 g of sodiumtriacetoxyborohydride was added, and the mixture was stirred at roomtemperature for 1 hour 40 minutes. Thereto were added water, a saturatedaqueous sodium hydrogen carbonate solution was added, and chloroform,the organic layer was separated, and the aqueous layer was extractedwith chloroform. The organic layer and the extract were combined, theresultant solution was washed with a saturated aqueous sodium chloridesolution and dried over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure. The resultant residue was purifiedby silica gel column chromatography using an eluent ofchloroform:methanol=50:1 to obtain 0.50 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl(1-(2-(7-methoxy-2-oxo-1,8-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamateas a white foam.

¹H-NMR (CDCl₃) δ: 1.41 (9H, s), 1.59-1.72 (4H, m), 2.09-2.25 (2H, m),2.64-2.72 (2H, m), 3.07-3.14 (2H, m), 3.99 (3H, s), 4.00-4.15 (1H, m),4.20-4.34 (6H, m), 4.57-4.63 (2H, m), 6.56 (1H, d, J=9.4 Hz), 6.60 (1H,d, J=8.3 Hz), 6.64-6.69 (1H, m), 6.71-6.73 (1H, m), 6.77 (1H, d, J=8.3Hz), 7.55 (1H, d, J=9.4 Hz), 7.71 (1H, d, J=8.3 Hz)

EXAMPLE 44

To 0.50 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl(1-(2-(7-methoxy-2-oxo-1,8-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate,15 mL of a 4 mol/L hydrogen chloride/ethyl acetate solution was added,and the mixture was stirred at room temperature for 43 hours. Thesolvent was distilled off under reduced pressure, methanol was added tothe resultant residue, and the solvent was distilled off under reducedpressure. Then, ethyl acetate was added to the resultant residue, andthe solid was filtered off to obtain 0.41 g of1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-1,8-naphthyridin-2(1H)-onehydrochloride as a light yellow solid.

¹H-NMR (D₂O) δ: 1.92-2.08 (2H, m), 2.45-2.58 (2H, m), 3.16-3.31 (2H, m),3.56-3.72 (3H, m), 3.96-4.10 (2H, m), 4.05 (3H, s), 4.17-4.28 (2H, m),4.33 (4H, s), 4.82-4.98 (2H, m), 6.64 (1H, d, J=9.3 Hz), 6.85 (1H, d,J=8.4 Hz), 6.95-7.06 (3H, m), 7.96 (1H, d, J=9.3 Hz), 8.04 (1H, d, J=8.4Hz)

EXAMPLE 45

To a solution of 0.20 g of1-(2-(4-(aminopiperidin-1-yl)ethyl)-7-methoxy-1,8-naphthyridin-2(1H)-onehydrochloride in 4 mL of methanol, 0.21 g of 28% sodium methoxide, 88 mgof 2,3-dihydro(1,4)dioxino(2,3-c)pyridine-7-carbaldehyde, 30 μL ofacetic acid and 67 mg of sodium cyanoborohydride were added, and themixture was stirred at room temperature for 6 hours 45 minutes. Theretowere added 27 mg of2,3-dihydro(1,4)dioxino(2,3-c)pyridine-7-carbaldehyde and 9 μL of aceticacid, and the mixture was stirred for 1 hour 30 minutes. After leavingovernight, the mixture was stirred at room temperature for 2 hours, 27mg of 2,3-dihydro(1,4)dioxino(2,3-c)pyridine-7-carbaldehyde and 9 μL ofacetic acid were added, and the mixture was stirred for 2 hours 30minutes. To the reaction mixture, water, a 1 mol/L aqueous sodiumhydroxide solution and chloroform were added, the organic layer wasseparated, and the aqueous layer was extracted with chloroform. Theorganic layer and the extract were combined, the resultant solution wasdried over anhydrous magnesium sulfate, and the solvent was distilledoff under reduced pressure. The resultant residue was purified by silicagel column chromatography using an eluent of chloroform:methanol=5:1,the oily substance thus obtained was dissolved in a 4 mol/L hydrogenchloride/ethyl acetate solution and methanol, and the solvent was thendistilled off under reduced pressure. Ethyl acetate was added to theresultant residue, and the solid was filtered off to obtain 0.18 g of1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-1,8-naphthyridin-2(1H)-onehydrochloride as a white solid.

¹H-NMR (D₂O) δ: 2.00-2.13 (2H, m), 2.52-2.62 (2H, m), 3.21-3.33 (2H, m),3.64-3.83 (3H, m), 3.98-4.15 (5H, m), 4.49-4.54 (2H, m), 4.59 (2H, s),4.64-4.68 (2H, m), 4.89-4.94 (2H, m), 6.65 (1H, d, J=9.5 Hz), 6.86 (1H,d, J=8.6 Hz), 7.56 (1H, s), 7.97 (1H, d, J=9.5 Hz), 8.05 (1H, d, J=8.6Hz), 8.43 (1H, s)

EXAMPLE 46

To 0.13 g of (3-oxopyrido(2,3-b)pyrazin-4(3H)-yl)acetaldehyde, asolution of 0.23 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate in 4mL of dichloromethane, 38 μL of acetic acid and 0.21 g of sodiumtriacetoxyborohydride were added, and the mixture was stirred at roomtemperature for 3 hours. Chloroform and a saturated aqueous sodiumhydrogen carbonate solution were added to the reaction mixture, theorganic layer was separated, and the aqueous layer was extracted withchloroform. The organic layer and the extract were combined, theresultant solution was washed with a saturated aqueous sodium chloridesolution and dried over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure. The resultant residue was purifiedby flash silica gel column chromatography using gradient elution withchloroform:methanol=100:0 to 90:10 to obtain 0.24 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(3-oxopyrido(2,3-b)pyrazin-4(3H)-yl)ethyl)piperidin-4-yl)carbamateas a light brown oily substance.

¹H-NMR (CDCl₃) δ: 1.41 (9H, s), 1.50-1.66 (4H, m), 1.98-2.20 (2H, m),2.64-2.72 (2H, m), 3.01-3.10 (2H, m), 3.95-4.14 (1H, m), 4.18-4.30 (6H,m), 4.54-4.61 (2H, m), 6.63-6.68 (1H, m), 6.69-6.72 (1H, m), 6.77 (1H,d, J=8.3 Hz), 7.31 (1H, dd, J=8.0, 4.6 Hz), 8.16 (1H, dd, J=8.0, 1.6Hz), 8.31 (1H, s), 8.56 (1H, dd, J=4.6, 1.6 Hz)

EXAMPLE 47

By the same technique as in Example2,4-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)pyrido(2,3-b)pyrazin-3(4H)-onehydrochloride was obtained from tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(3-oxopyrido(2,3-b)pyrazin-4(3H)-yl)ethyl)piperidin-4-yl)carbamate.

¹H-NMR (D₂O) δ: 1.90-2.05 (2H, m), 2.45-2.55 (2H, m), 3.16-3.32 (2H, m),3.55-3.71 (3H, m), 3.96-4.07 (2H, m), 4.21 (2H, s), 4.33 (4H, s),4.88-4.93 (2H, m), 6.95-7.04 (3H, m), 7.58 (1H, dd, J=8.0, 4.8 Hz), 8.35(1H, dd, J=8.0, 1.5 Hz), 8.39 (1H, s), 8.71 (1H, dd, J=4.8, 1.5 Hz)

EXAMPLE 48

By the same technique as in Example 1, tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamatewas obtained from (2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde andtert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(piperidin-4-yl)carbamate.

¹H-NMR (CDCl₃-D₂O) δ: 1.34-1.52 (9H, m), 1.60-1.70 (4H, m), 2.08-2.22(2H, m), 2.58-2.63 (2H, m), 2.95-3.04 (2H, m), 4.00-4.20 (1H, m),4.24-4.40 (8H, m), 6.74 (1H, s), 6.91 (1H, d, J=9.8 Hz), 7.46 (1H, dd,J=8.6, 4.5 Hz), 7.76 (1H, d, J=8.6 Hz), 7.91 (1H, d, J=9.8 Hz), 8.05(1H, s), 8.53-8.56 (1H, m)

EXAMPLE 49

By the same technique as in Example2,1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-1,5-naphthyridin-2(1H)-onehydrochloride was obtained from tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate.

¹H-NMR (DMSO-d₆-D₂O) δ: 2.02-2.18 (2H, m), 2.36-2.48 (2H, m), 3.12-3.24(2H, m), 3.30-3.50 (3H, m), 3.72-3.88 (2H, m), 4.36-4.46 (4H, m), 4.53(2H, s), 4.65-4.73 (2H, m), 7.00 (1H, d, J=9.8 Hz), 7.62 (1H, s), 7.76(1H, dd, J=8.6, 4.6 Hz), 8.08 (1H, d, J=9.8 Hz), 8.42 (1H, d, J=8.6 Hz),8.50 (1H, s), 8.65 (1H, d, J=4.6 Hz)

EXAMPLE 50

By the same technique as in Example 30,6-(((1-(2-(2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)amino)methyl)-2H-pyrido(3,2-b)(1,4)thiazin-3(4H)-onewas obtained from1-(2-(4-aminopiperidin-1-yl)ethyl)-1,5-naphthyridin-2(1H)-onehydrochloride and3-oxo-3,4-dihydro-2H-pyrido(3,2-b)(1,4)thiazine-6-carbaldehyde.

¹H-NMR (CDCl₃-D₂O) δ: 1.36-1.50 (2H, m), 1.82-1.92 (2H, m), 2.12-2.20(2H, m), 2.44-2.54 (1H, m), 2.60-2.64 (2H, m), 2.90-3.00 (2H, m), 3.44(2H, s), 3.79 (2H, s), 4.34-4.39 (2H, m), 6.89 (1H, d, J=9.6 Hz), 6.94(1H, d, J=7.8 Hz), 7.44 (1H, dd, J=8.5, 4.4 Hz), 7.54 (1H, d, J=7.8 Hz),7.78 (1H, d, J=8.5 Hz), 7.89 (1H, d, J=9.6 Hz), 8.52 (1H, d, J=4.4 Hz)

EXAMPLE 51

By the same technique as in Example 41,(2-oxopyrido(2,3-b)pyrazin-1(2H)-yl)acetaldehyde was obtained from1-(1,3-dioxolan-2-ylmethyl)pyrido(2,3-b)pyrazin-2(1H)-one. Tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(2-oxopyrido(2,3-b)pyrazin-1(2H)-yl)ethyl)piperidin-4-yl)carbamatewas obtained from (2-oxopyrido(2,3-b)pyrazin-1(2H)-yl)acetaldehyde andtert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate.

¹H-NMR (CDCl₃) δ: 1.42 (9H, s), 1.53-1.72 (4H, m), 2.02-2.23 (2H, m),2.49-2.66 (2H, m), 2.90-3.00 (2H, m), 3.94-4.13 (1H, m), 4.20-4.35 (8H,m), 6.64-6.80 (3H, m), 7.50 (1H, dd, J=8.6, 4.5 Hz), 7.77 (1H, dd,J=8.6, 1.3 Hz), 8.53 (1H, s), 8.66 (1H, dd, J=4.5, 1.3 Hz)

EXAMPLE 52

By the same technique as in Example2,1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)pyrido(2,3-b)pyrazin-2(1H)-onehydrochloride was obtained from tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(2-oxopyrido(2,3-b)pyrazin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate.

¹H-NMR (DMSO-d₆) δ: 1.94-2.12 (2H, m), 2.27-2.40 (2H, m), 3.00-3.86 (7H,m), 4.02-4.13 (2H, m), 4.25 (4H, s), 4.60-4.69 (2H, m), 6.91 (1H, d,J=8.3 Hz), 7.00-7.07 (1H, m), 7.15 (1H, s), 7.66-7.79 (1H, m), 8.32-8.38(1H, m), 8.50 (1H, s), 8.63 (1H, d, J=4.4 Hz), 9.40-9.60 (2H, broad),10.65-10.85 (1H, broad)

EXAMPLE 53

By the same technique as in Example 41,(3-oxopyrido(3,4-b)pyrazin-4(3H)-yl)acetaldehyde was obtained from4-(1,3-dioxolan-2-ylmethyl)pyrido(3,4-b)pyrazin-3(4H)-one. Tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(3-oxopyrido(3,4-b)pyrazin-4(3H)-yl)ethyl)piperidin-4-yl)carbamatewas obtained from (3-oxopyrido(3,4-b)pyrazin-4(3H)-yl)acetaldehyde andtert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate.

¹H-NMR (CDCl₃) δ: 1.41 (9H, s), 1.53-1.69 (4H, m), 2.06-2.26 (2H, m),2.65-2.72 (2H, m), 2.93-3.02 (2H, m), 3.96-4.12 (1H, m), 4.12-4.34 (6H,m), 4.34-4.40 (2H, m), 6.63-6.80 (3H, m), 7.74 (1H, d, J=5.1 Hz), 8.45(1H, s), 8.58 (1H, d, J=5.1 Hz), 8.87 (1H, s)

EXAMPLE 54

To a solution of 10 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(3-oxopyrido(3,4-b)pyrazin-4(3H)-yl)ethyl)piperidin-4-yl)carbamatein 1 mL of dichloromethane, 1.0 mL of trifluoroacetic acid was added atroom temperature. The mixture was stirred at the same temperature for 4hours, and the solvent was distilled off under reduced pressure. Theresultant residue was charged with chloroform and water and adjusted topH 0.5 with 1 mol/L hydrochloric acid, and the aqueous layer wasseparated. Chloroform was added to the aqueous layer, and the aqueouslayer was adjusted to pH 12 with a 1 mol/L aqueous sodium hydroxidesolution. The organic layer was separated, and the aqueous layer wasextracted with chloroform. The organic layer and the extract werecombined, the resultant solution was washed with a saturated aqueoussodium chloride solution and dried over anhydrous magnesium sulfate, andthe solvent was distilled off under reduced pressure to obtain 2 mg of4-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)pyrido(3,4-b)pyrazin-3(4H)-oneas a light brown oily substance.

¹H-NMR (CDCl₃) δ: 1.35-1.48 (2H, m), 1.83-1.95 (2H, m), 2.13-2.23 (2H,m), 2.50-2.65 (1H, m), 2.69-2.75 (2H, m), 2.91-3.00 (2H, m), 3.71 (2H,s), 4.24 (4H, s), 4.37-4.44 (2H, m), 6.76-6.86 (3H, m), 7.74 (1H, d,J=5.1 Hz), 8.45 (1H, s), 8.58 (1H, d, J=5.1 Hz), 8.90 (1H, s)

EXAMPLE 55

To a suspension of 0.21 g of4-(2-(4-aminopiperidin-1-yl)ethyl)-6-methoxypyrido(2,3-b)pyrazin-3(4H)-onehydrochloride in 5 mL of methanol, 0.22 g of a 28% sodiummethoxide/methanol solution, 0.11 g of3-oxo-3,4-dihydro-2H-pyrido(3,2-b)(1,4)thiazine-6-carbaldehyde, 32 μL ofacetic acid and 70 mg of sodium cyanoborohydride were added, and themixture was stirred at room temperature for 3 hours. Chloroform and asaturated aqueous sodium hydrogen carbonate solution were added to thereaction mixture, the organic layer was separated, and the aqueous layerwas extracted with chloroform. The organic layer and the extract werecombined, the resultant solution was washed with a saturated aqueoussodium chloride solution and dried over anhydrous magnesium sulfate, andthe solvent was distilled off under reduced pressure. The resultantresidue was purified by basic silica gel column chromatography using aneluent of chloroform:methanol=10:1. Diethyl ether and hexane were addedto the resultant residue, and the solid was filtered off to obtain 0.13g of6-(((1-(2-(6-methoxy-3-oxopyrido(2,3-b)pyrazin-4(3H)-yl)ethyl)piperidin-4-yl)amino)methyl)-2H-pyrido(3,2-b)(1,4)thiazin-3(4H)-oneas a light brown solid.

¹H-NMR (CDCl₃) δ: 1.34-1.47 (2H, m), 1.82-1.93 (2H, m), 2.12-2.22 (2H,m), 2.46-2.56 (1H, m), 2.71-2.78 (2H, m), 3.00-3.08 (2H, m), 3.46 (2H,s), 3.83 (2H, s), 4.03 (3H, s), 4.54-4.61 (2H, m), 6.72 (1H, d, J=8.7Hz), 6.97 (1H, d, J=7.8 Hz), 7.56 (1H, d, J=7.8 Hz), 8.01 (1H, d, J=8.7Hz), 8.14 (1H, s), 8.60-8.80 (1H, broad)

EXAMPLE 56

By the same technique as in Example 1, tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(7-methyl-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamatewas obtained from (7-methyl-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehydeand tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(piperidin-4-yl)carbamate.

¹H-NMR (CDCl₃) δ: 1.39 (9H, s), 1.40-1.72 (4H, m), 2.08-2.25 (2H, m),2.49 (3H, s), 2.56-2.63 (2H, m), 2.97-3.06 (2H, m), 4.02-4.20 (1H, m),4.24-4.48 (8H, m), 6.73 (1H, s), 6.83 (1H, d, J=9.6 Hz), 7.50-7.54 (1H,m), 7.86 (1H, d, J=9.6 Hz), 8.05 (1H, s), 8.36-8.39 (1H, m)

EXAMPLE 57

By the same technique as in Example2,1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methyl-1,5-naphthyridin-2(1H)-onehydrochloride was obtained from tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(7-methyl-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate.

¹H-NMR (D₂O) δ: 2.02-2.16 (2H, m), 2.51-2.63 (2H, m), 2.65 (3H, s),3.25-3.37 (2H, m), 3.63-3.69 (2H, m), 3.71-3.82 (1H, m), 3.99-4.08 (2H,m), 4.46-4.51 (2H, m), 4.54 (2H, s), 4.59-4.63 (2H, m), 4.76-4.86 (2H,m), 7.17 (1H, d, J=9.9 Hz), 7.48 (1H, s), 8.18 (1H, d, J=9.9 Hz), 8.38(1H, s), 8.40 (1H, s), 8.64 (1H, m)

EXAMPLE 58

By the same technique as in Example 1, tert-butyl(3,4-dihydro-2H-(1,4)dioxepino(2,3-c)pyridin-8-ylmethyl)(1-(2-(7-methoxy-2-oxopyrido(2,3-b)pyrazin-1(2H)-yl)ethyl)piperidin-4-yl)carbamatewas obtained from(7-methoxy-2-oxopyrido(2,3-b)pyrazin-1(2H)-yl)acetaldehyde andtert-butyl(3,4-dihydro-2H-(1,4)dioxepino(2,3-c)pyridin-8-ylmethyl)(piperidin-4-yl)carbamate.

¹H-NMR (CDCl₃) δ: 1.29-1.72 (4H, m), 1.37 (9H, s), 2.06-2.28 (4H, m),2.58-2.66 (2H, m), 2.91-3.01 (2H, m), 3.99 (3H, s), 4.06-4.16 (1H, m),4.20-4.38 (8H, m), 6.77 (1H, s), 7.15-7.21 (1H, m), 8.13 (1H, s), 8.33(1H, s), 8.36 (1H, d, J=2.7 Hz)

EXAMPLE 59

To a solution of 87 mg of tert-butyl(3,4-dihydro-2H-(1,4)dioxepino(2,3-c)pyridin-8-ylmethyl)(1-(2-(7-methoxy-2-oxopyrido(2,3-b)pyrazin-1(2H)-yl)ethyl)piperidin-4-yl)carbamatein 2 mL of dichloromethane, 2 mL of trifluoroacetic acid was added, andthe mixture was stirred at room temperature for 1 hour. The solvent wasdistilled off under reduced pressure, and chloroform and water wereadded thereto. The aqueous layer was separated and adjusted to pH 13.1with a 20% aqueous sodium hydroxide solution. Chloroform was addedthereto, the organic layer was separated, and the aqueous layer wasextracted with chloroform. The organic layer and the extract werecombined, the resultant solution was washed sequentially with water anda saturated aqueous sodium chloride solution and dried over anhydrousmagnesium sulfate, and the solvent was distilled off under reducedpressure to obtain 54 mg of1-(2-(4-((3,4-dihydro-2H-(1,4)dioxepino(2,3-c)pyridin-8-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxypyrido(2,3-b)pyrazin-2(1H)-oneas a yellowish brown oily substance.

¹H-NMR (CDCl₃) δ: 1.36-1.48 (2H, m), 1.86-1.95 (2H, m), 2.13-2.28 (2H,m), 2.25 (2H, quint, J=5.8 Hz), 2.48-2.59 (1H, m), 2.64-2.70 (2H, m),2.91-2.98 (2H, m), 3.80 (2H, s), 4.00 (3H, s), 4.24 (2H, t, J=5.8 Hz),4.28-4.36 (2H, m), 4.33 (2H, t, J=5.8 Hz), 6.85 (1H, s), 7.24-7.28 (1H,m), 8.18 (1H, s), 8.34 (1H, s), 8.36 (1H, d, J=2.7 Hz)

EXAMPLE 60

By the same technique as in Example8,1-(2-(4-((3,4-dihydro-2H-(1,4)dioxepino(2,3-c)pyridin-8-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxypyrido(2,3-b)pyrazin-2(1H)-onehydrochloride was obtained from1-(2-(4-((3,4-dihydro-2H-(1,4)dioxepino(2,3-c)pyridin-8-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxypyrido(2,3-b)pyrazin-2(1H)-one.

¹H-NMR (D₂O) δ: 1.97-2.10 (2H, m), 2.31 (2H, quint, J=5.7 Hz), 2.49-2.57(2H, m), 3.21-3.31 (2H, m), 3.61-3.71 (3H, m), 3.95-4.04 (2H, m), 4.05(3H, s), 4.36 (2H, t, J=5.9 Hz), 4.37 (2H, s), 4.48 (2H, t, J=5.9 Hz),4.73-4.87 (2H, m), 7.20 (1H, s), 7.49 (1H, d, J=2.6 Hz), 8.28 (1H, s),8.34 (1H, s), 8.42 (1H, d, J=2.6 Hz)

EXAMPLE 61

To a solution of 0.46 g of ethyl4-(3-(2-oxo-1,8-naphthyridin-1(2H)-yl)propyl)piperidine-4-carboxylate in10 mL of N,N-dimethylformamide, 0.37 g of potassium carbonate and 0.31 gof 2-((2-bromoethyl)thio)thiophene were added, and the mixture wasstirred at 50 to 70° C. for 2 hours 10 minutes. The reaction mixture wascooled to room temperature, then, water and ethyl acetate were addedthereto, the organic layer was separated, and the aqueous layer wasextracted with ethyl acetate. The organic layer and the extract werecombined, the resultant solution was dried over anhydrous magnesiumsulfate, and the solvent was distilled off under reduced pressure. Theresultant residue was purified by silica gel column chromatography usingan eluent of chloroform:methanol 50:1 to obtain 0.39 g of ethyl4-(3-(2-oxo-1,8-naphthyridin-1(2H)-yl)propyl)-1-(2-(2-thienylthio)ethyl)piperidine-4-carboxylateas a yellow oily substance.

¹H-NMR (CDCl₃) δ: 1.20 (3H, t, J=7.1 Hz), 1.42-1.52 (2H, m), 1.60-1.69(4H, m), 2.00-2.14 (4H, m), 2.52-2.58 (2H, m), 2.64-2.71 (2H, m),2.85-2.91 (2H, m), 4.10 (2H, q, J=7.1 Hz), 4.42-4.47 (2H, m), 6.71 (1H,d, J=9.4 Hz), 6.93-6.97 (1H, m), 7.08-7.10 (1H, m), 7.15 (1H, dd, J=7.6,4.6 Hz), 7.30-7.33 (1H, m), 7.61 (1H, d, J=9.4 Hz), 7.84 (1H, dd, J=7.6,1.7 Hz), 8.55 (1H, dd, J=4.6, 1.7 Hz)

EXAMPLE 62

To a solution of 0.30 g of ethyl4-(3-(2-oxo-1,8-naphthyridin-1(2H)-yl)propyl)-1-(2-(2-thienylthio)ethyl)piperidine-4-carboxylatein 5 mL of ethanol, 1.7 mL of a 20% aqueous sodium hydroxide solutionwas added at room temperature, and the mixture was heated under refluxwhile stirring for 7 hours. Thereto was further added 0.3 mL of a 20%aqueous sodium hydroxide solution, and mixture was stirred for 1 hour,and then cooled to room temperature, and the solvent was distilled offunder reduced pressure. The resultant residue was charged with water andadjusted to pH 6.5 with 1 mol/L hydrochloric acid. The solid wasfiltered off to obtain 0.22 g of4-(3-(2-oxo-1,8-naphthyridin-1(2H)-yl)propyl)-1-(2-(2-thienylthio)ethyl)piperidine-4-carboxylicacid as a white solid.

¹H-NMR (DMSO-d₆) δ: 1.24-1.34 (2H, m), 1.45-1.59 (4H, m), 1.86-1.98 (4H,m), 2.42-2.47 (2H, m), 2.55-2.62 (2H, m), 2.87-2.92 (2H, m), 4.30-4.35(2H, m), 6.69 (1H, d, J=9.5 Hz), 7.03 (1H, dd, J=5.1, 3.6 Hz), 7.15-7.17(1H, m), 7.32 (1H, dd, J=7.6, 4.8 Hz), 7.59 (1H, d, J=5.1 Hz), 7.95 (1H,d, J=9.5 Hz), 8.16-8.20 (1H, m), 8.63-8.66 (1H, m)

EXAMPLE 63

By the same technique as in Example 61, ethyl4-(3-(2-oxo-1,7-naphthyridin-1(2H)-yl)propyl)-1-(2-(2-thienylthio)ethyl)piperidine-4-carboxylatewas obtained from ethyl4-(3-(2-oxo-1,7-naphthyridin-1(2H)-yl)propyl)piperidine-4-carboxylateand 2-(2-bromoethylthio)thiophene.

¹H-NMR (CDCl₃) δ: 1.21 (3H, t, J=7.2 Hz), 1.40-1.80 (6H, m), 2.00-2.18(4H, m), 2.50-2.60 (2H, m), 2.62-2.74 (2H, m), 2.84-2.92 (2H, m), 4.12(2H, q, J=7.2 Hz), 4.24-4.31 (2H, m), 6.88 (1H, d, J=9.5 Hz), 6.95 (1H,dd, J=5.3, 3.6 Hz), 7.10 (1H, dd, J=3.6, 1.2 Hz), 7.32 (1H, dd, J=5.3,1.2 Hz), 7.42 (1H, d, J=5.0 Hz), 7.64 (1H, d, J=9.5 Hz), 8.44 (1H, d,J=5.0 Hz), 8.74 (1H, s)

By the same technique as in Example 62,4-(3-(2-oxo-1,7-naphthyridin-1(2H)-yl)propyl)-1-(2-(2-thienylthio)ethyl)piperidine-4-carboxylicacid was obtained from ethyl4-(3-(2-oxo-1,7-naphthyridin-1(2H)-yl)propyl)-1-(2-(2-thienylthio)ethyl)piperidine-4-carboxylate.

¹H-NMR (DMSO-d₆) δ: 1.22-1.36 (2H, m), 1.48-1.60 (4H, m), 1.86-2.02 (4H,m), 2.40-2.63 (4H, m), 2.86-2.93 (2H, m), 4.22-4.28 (2H, m), 6.85 (1H,d, J=9.5 Hz), 7.03 (1H, dd, J=5.4, 3.5 Hz), 7.16 (1H, dd, J=3.5, 1.1Hz), 7.58 (1H, dd, J=5.4, 1.1 Hz), 7.69 (1H, d, J=5.0 Hz), 7.95 (1H, d,J=9.5 Hz), 8.42 (1H, d, J=5.0 Hz), 8.93 (1H, s)

EXAMPLE 64

By the same technique as in Example 1, tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(6-fluoro-3-oxopyrido(2,3-b)pyrazin-4(3H)-yl)ethyl)piperidin-4-yl)carbamatewas obtained from tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(piperidin-4-yl)carbamateand (6-fluoro-3-oxopyrido(2,3-b)pyrazin-4(3H)-yl)acetaldehyde.

¹H-NMR (CDCl₃) δ: 1.30-1.70 (4H, m), 1.38 (9H, s), 2.00-2.15 (2H, m),2.64-2.70 (2H, m), 3.01-3.08 (2H, m), 4.02-4.16 (1H, m), 4.25-4.33 (6H,m), 4.42-4.48 (2H, m), 6.71 (1H, s), 6.89 (1H, dd, J=8.4, 2.8 Hz), 8.03(1H, s), 8.21-8.27 (2H, m)

EXAMPLE 65

To a solution of 90 mg of tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(6-fluoro-3-oxopyrido(2,3-b)pyrazin-4(3H)-yl)ethyl)piperidin-4-yl)carbamatein 1 mL of methanol, 1 mL of a 4 mol/L hydrogen chloride/ethyl acetatesolution was added, and the mixture was stirred at room temperature for1 hour. The solid was filtered off to obtain 76 mg of4-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-6-fluoropyrido(2,3-b)pyrazin-3(4H)-onehydrochloride.

¹H-NMR (DMSO-d₆) δ: 1.97-2.09 (2H, m), 2.28-2.37 (2H, m), 3.00-3.14 (2H,m), 3.26-3.36 (1H, m), 3.39-3.57 (2H, m), 3.80-4.00 (2H, m), 4.19-4.27(2H, m), 4.33-4.45 (4H, m), 4.55-4.63 (2H, m), 7.25 (1H, dd, J=8.5, 2.2Hz), 7.32 (1H, s), 8.26 (1H, s), 8.33 (1H, s), 8.46-8.51 (1H, m),9.70-9.90 (2H, broad), 10.35-10.55 (1H, broad)

EXAMPLE 66

By the same technique as in Example 1, tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(7-methoxy-2-oxopyrido(2,3-b)pyrazin-1(2H)-yl)ethyl)piperidin-4-yl)carbamatewas obtained from(7-methoxy-2-oxopyrido(2,3-b)pyrazin-1(2H)-yl)acetaldehyde andtert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(piperidin-4-yl)carbamate.

¹H-NMR (CDCl₃) δ: 1.34-1.70 (4H, m), 1.39 (9H, s), 2.08-2.24 (2H, m),2.60-2.66 (2H, m), 2.92-3.00 (2H, m), 3.99 (3H, s), 4.03-4.15 (1H, m),4.23-4.37 (8H, m), 6.73 (1H, s), 7.18 (1H, d, J=2.4 Hz), 8.05 (1H, s),8.33 (1H, s), 8.36 (1H, d, J=2.4 Hz)

EXAMPLE 67

By the same technique as in Example 59,1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxypyrido(2,3-b)pyrazin-2(1H)-onewas obtained from tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(7-methoxy-2-oxopyrido(2,3-b)pyrazin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate.

¹H-NMR (CDCl₃) δ: 1.37-1.48 (2H, m), 1.86-1.99 (2H, m), 2.13-2.23 (2H,m), 2.48-2.58 (1H, m), 2.64-2.69 (2H, m), 2.91-2.98 (2H, m), 3.78 (2H,s), 4.00 (3H, s), 4.25-4.35 (6H, m), 6.81 (1H, s), 7.26 (1H, d, J=2.6Hz), 8.10 (1H, s), 8.34 (1H, s), 8.36 (1H, d, J=2.6 Hz)

EXAMPLE 68

By the same technique as in Example8,1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxypyrido(2,3-b)pyrazin-2(1H)-onehydrochloride was obtained from1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxypyrido(2,3-b)pyrazin-2(1H)-one.

¹H-NMR (D₂O) δ: 1.96-2.10 (2H, m), 2.49-2.57 (2H, m), 3.21-3.32 (2H, m),3.61-3.72 (3H, m), 3.95-4.04 (2H, m), 4.06 (3H, s), 4.39 (2H, s),4.40-4.54 (4H, m), 4.75-4.81 (2H, m), 7.25 (1H, s), 7.48-7.51 (1H, m),8.24 (1H, s), 8.34 (1H, s), 8.41-8.44 (1H, m)

EXAMPLE 69

By the same technique as in Example 1, tert-butyl(1-(2-(6-chloro-3-oxopyrido(2,3-b)pyrazin-4(3H)-yl)ethyl)piperidin-4-yl)(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)carbamatewas obtained from tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(piperidin-4-yl)carbamateand (6-chloro-3-oxopyrido(2,3-b)pyrazin-4(3H)-yl)acetaldehyde.

¹H-NMR (CDCl₃) δ: 1.38 (9H, s), 1.40-1.65 (4H, m), 1.97-2.15 (2H, m),2.64-2.70 (2H, m), 3.03-3.10 (2H, m), 4.02-4.14 (1H, m), 4.25-4.34 (6H,m), 4.46-4.52 (2H, m), 6.70 (1H, s), 7.26 (1H, d, J=8.2 Hz), 8.02 (1H,s), 8.09 (1H, d, J=8.2 Hz), 8.28 (1H, s)

EXAMPLE 70

To a solution of 0.11 g of tert-butyl(1-(2-(6-chloro-3-oxopyrido(2,3-b)pyrazin-4(3H)-yl)ethyl)piperidin-4-yl)(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)carbamatein 3 mL of dioxane, 25 mg of tert-butyl carbamate and 82 mg of cesiumcarbonate were added. Thereto were added 2.5 mg oftris(dibenzylideneacetate)dipalladium(0) and 3.1 mg of4,5-bis(diphenylphosphino)-9,9-dimethylxanthene under an argonatmosphere. The mixture was stirred at 80 to 90° C. for 2 hours under anargon atmosphere. The insoluble substance was filtered off, and thesolvent was distilled off under reduced pressure. The resultant residuewas purified by basic silica gel column chromatography using an eluentof chloroform:methanol=20:1 to obtain 78 mg of tert-butyl(1-(2-(6-((tert-butoxycarbonyl)amino)-3-oxopyrido(2,3-b)pyrazin-4(3H)-yl)ethyl)piperidin-4-yl)(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)carbamateas a light brown oily substance.

¹H-NMR (CDCl₃) δ: 1.35-1.70 (4H, m), 1.38 (9H, s), 1.56 (9H, s),2.03-2.19 (2H, m), 2.58-2.64 (2H, m), 3.00-3.04 (2H, m), 4.06-4.19 (1H,m), 4.24-4.38 (6H, m), 4.40-4.48 (2H, m), 6.72 (1H, s), 7.37 (1H, s),7.96 (1H, d, J=8.8 Hz), 8.05 (1H, s), 8.09 (1H, d, J=8.8 Hz), 8.15 (1H,s)

EXAMPLE 71

By the same technique as in Example 65,6-amino-4-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)pyrido(2,3-b)pyrazin-3(4H)-onehydrochloride was obtained from tert-butyl(1-(2-(6-((tert-butoxycarbonyl)amino)-3-oxopyrido(2,3-b)pyrazin-4(3H)-yl)ethyl)piperidin-4-yl)(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)carbamate.

¹H-NMR (DMSO-d₆-D₂O) δ: 1.85-1.97 (2H, m), 2.32-2.41 (2H, m), 3.04-3.14(2H, m), 3.33-3.48 (3H, m), 3.92-4.00 (2H, m), 4.26 (2H, s), 4.35-4.46(4H, m), 4.54-4.60 (2H, m), 6.56 (1H, d, J=8.8 Hz), 7.31 (1H, s), 7.83(1H, d, J=8.8 Hz), 7.87 (1H, s), 8.30 (1H, s)

EXAMPLE 72

(1) To 98 mg of4-(1,3-dioxolan-2-ylmethyl)-6-(1H-1,2,4-triazol-1-yl)pyrido(2,3-b)pyrazin-3(4H)-one,3 mL of an 80% aqueous trifluoroacetic acid solution was added, and themixture was stirred at room temperature for 6 hours 30 minutes. Theretowere added water and ethyl acetate, and the mixture was neutralized witha saturated aqueous sodium hydrogen carbonate solution and an aqueoussodium hydroxide solution. The organic layer was separated, and sodiumchloride was added to the aqueous layer, and the mixture was extractedwith chloroform. The organic layer and the extract were combined, theresultant solution was dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure to obtain 0.12 g of(3-oxo-6-(1H-1,2,4-triazol-1-yl)pyrido(2,3-b)pyrazin-4(3H)-yl)acetaldehydeas a light red solid.

(2) To a solution of 48 mg of tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(piperidin-4-yl)carbamatein 2 mL of methanol, 50 mg of(3-oxo-6-(1H-1,2,4-triazol-1-yl)pyrido(2,3-b)pyrazin-4(3H)-yl)acetaldehyde,2.5 mL of dichloromethane and 20 μL of acetic acid were added, and themixture was stirred at room temperature for 40 minutes. To the reactionmixture, 9.0 mg of sodium cyanoborohydride was added, and the mixturewas stirred at room temperature for 1 hour 30 minutes. Thereto wereadded a saturated aqueous sodium hydrogen carbonate solution andchloroform, the organic layer was separated, washed sequentially withwater and a saturated aqueous sodium chloride solution and dried overanhydrous magnesium sulfate, and the solvent was distilled off underreduced pressure. The resultant residue was purified by silica gelcolumn chromatography using an eluent of chloroform:methanol=50:1 toobtain 35 mg of tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(3-oxo-6-(1H-1,2,4-triazol-1-yl)pyrido(2,3-b)pyrazin-4(3H)-yl)ethyl)piperidin-4-yl)carbamateas a light yellow oily substance.

¹H-NMR (CDCl₃) δ: 1.38 (9H, s), 1.30-1.70 (4H, m), 2.05-2.21 (2H, m),2.69-2.75 (2H, m), 3.00-3.08 (2H, m), 4.04-4.16 (1H, m), 4.25-4.34 (6H,m), 4.52-4.58 (2H, m), 6.70 (1H, s), 7.92 (1H, d, J=8.6 Hz), 8.02 (1H,s), 8.14 (1H, s), 8.31 (1H, s), 8.35 (1H, d, J=8.6 Hz), 9.09 (1H, s)

EXAMPLE 73

By the same technique as in Example 65,4-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-6-(1H-1,2,4-triazol-1-yl)pyrido(2,3-b)pyrazin-3(4H)-onehydrochloride was obtained from tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(3-oxo-6-(1H-1,2,4-triazol-1-yl)pyrido(2,3-b)pyrazin-4(3H)-yl)ethyl)piperidin-4-yl)carbamate.

¹H-NMR (DMSO-d₆) δ: 1.97-2.34 (4H, m), 3.02-3.14 (2H, m), 3.24-3.36 (1H,m), 3.40-3.50 (2H, m), 3.80-4.00 (2H, m), 4.19-4.26 (2H, m), 4.30-4.45(4H, m), 4.80-4.83 (2H, m), 7.27 (1H, s), 7.90 (1H, d, J=8.4 Hz), 8.25(1H, s), 8.35 (1H, s), 8.41 (1H, s), 8.52 (1H, d, J=8.4 Hz), 9.55-9.80(2H, broad), 9.94 (1H, s), 10.95-11.00 (1H, m)

EXAMPLE 74

By the same technique as in Example 1, ethyl(2E)-3-(5-(2-(4-((tert-butoxycarbonyl)(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)acrylatewas obtained from ethyl(2E)-3-(6-oxo-5-(2-oxoethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)acrylateand tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(piperidin-4-yl)carbamate.

¹H-NMR (CDCl₃) δ: 1.30-1.75 (13H, m), 1.38 (3H, t, J=7.2 Hz), 2.10-2.27(2H, m), 2.58-2.65 (2H, m), 2.98-3.06 (2H, m), 4.04-4.20 (1H, m),4.24-4.46 (10H, m), 6.62 (1H, d, J=16.2 Hz), 6.72-6.74 (1H, broad), 6.93(1H, d, J=9.8 Hz), 7.75 (1H, d, J=16.2 Hz), 7.78 (1H, s), 7.89 (1H, d,J=9.8 Hz), 8.05 (1H, s), 8.68 (1H, d, J=1.2 Hz)

EXAMPLE 75

By the same technique as in Example 54, ethyl(2E)-3-(5-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)acrylatewas obtained from ethyl (2E)-3-(5-(2-(4-((tert-butoxycarbonyl)(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)acrylate.

¹H-NMR (CDCl₃) δ: 1.35-1.54 (2H, m), 1.37 (3H, t, J=7.2 Hz), 1.85-2.00(2H, m), 2.12-2.28 (2H, m), 2.46-2.74 (3H, m), 2.93-3.04 (2H, m), 3.80(2H, s), 4.24-4.44 (8H, m), 6.65 (1H, d, J=16.1 Hz), 6.82 (1H, s), 6.93(1H, d, J=9.8 Hz), 7.76 (1H, d, J=16.1 Hz), 7.87-7.92 (1H, broad), 7.89(1H, d, J=9.8 Hz), 8.10 (1H, s), 8.68 (1H, d, J=1.7 Hz)

EXAMPLE 76

By the same technique as in Example 1, tert-butyl(1-(2-(7-chloro-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)carbamatewas obtained from (7-chloro-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehydeand tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(piperidin-4-yl)carbamate.

¹H-NMR (CDCl₃) δ: 1.35-1.55 (13H, m), 2.08-2.27 (2H, m), 2.58-2.65 (2H,m), 2.93-3.02 (2H, m), 4.05-4.20 (1H, m), 4.22-4.50 (8H, m), 6.72 (1H,s), 6.88 (1H, d, J=9.8 Hz), 7.78-7.82 (1H, m), 7.86 (1H, d, J=9.8 Hz),8.05 (1H, s), 8.46 (1H, d, J=2.0 Hz)

EXAMPLE 77

By the same technique as in Example 2,7-chloro-1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-1,5-naphthyridin-2(1H)-onehydrochloride was obtained from tert-butyl(1-(2-(7-chloro-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)carbamate.

¹H-NMR (D₂O) δ: 2.00-2.14 (2H, m), 2.51-2.61 (2H, m), 3.22-3.36 (2H, m),3.60-3.80 (3H, m), 3.97-4.07 (2H, m), 4.45-4.50 (2H, m), 4.52 (2H, s),4.57-4.62 (2H, m), 4.72-4.82 (2H, m), 7.03 (1H, d, J=9.8 Hz), 7.44 (1H,s), 8.08 (1H, d, J=9.8 Hz), 8.19-8.22 (1H, m), 8.36 (1H, s), 8.61 (1H,d, J=1.7 Hz)

EXAMPLE 78

To a suspension of 0.22 g of1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-onehydrochloride in 7 mL of methanol, 66 mg of sodium cyanoborohydride, 64μL of 3-fluoro-4-methylbenzaldehyde, 0.30 g of a 28% sodiummethoxide/methanol solution and 30 μL of acetic acid were added, and themixture was stirred at room temperature for 3 hours. Thereto was added22 mg of 3-fluoro-4-methylbenzaldehyde, and the mixture was stirred atthe same temperature for 1 hour. Thereto was further added 33 mg ofsodium cyanoborohydride, and the mixture was stirred at the sametemperature for 1 hour. A saturated aqueous sodium hydrogen carbonatesolution was added thereto, and the solvent was distilled off underreduced pressure. Thereto was added chloroform, the organic layer wasseparated, and the aqueous layer was extracted with chloroform. Theorganic layer and the extract were combined, the resultant solution waswashed sequentially with water and a saturated aqueous sodium chloridesolution, and dried over anhydrous magnesium sulfate, and the solventwas distilled off under reduced pressure. The resultant residue waspurified by basic silica gel column chromatography using an eluent ofchloroform:methanol=9:1 to obtain 20 mg of1-(2-(4-((3-fluoro-4-methylbenzyl)amino)piperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-oneas a colorless oily substance.

¹H-NMR (CDCl₃) δ: 1.36-1.57 (2H, m), 1.86-1.94 (2H, m), 2.13-2.22 (2H,m), 2.25 (3H, s), 2.48-2.56 (1H, m), 2.61-2.68 (2H, m), 2.94-3.01 (2H,m), 3.77 (2H, s), 3.97 (3H, s), 4.33-4.39 (2H, m), 6.74 (1H, d, J=9.6Hz), 6.95-7.01 (2H, m), 7.11 (1H, t, J=8.0 Hz), 7.23 (1H, d, J=2.3 Hz),7.84 (1H, d, J=9.6 Hz), 8.28 (1H, d, J=2.3 Hz)

EXAMPLE 79

To a solution of 297 mg of1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-oneand 159 mg of3-oxo-3,4-dihydro-2H-pyrido(3,2-b)(1,4)oxazine-6-carbaldehyde in 4 mL ofchloroform and 1 mL of methanol, 0.11 mL of acetic acid was added, andthe mixture was stirred at room temperature for 16 hours. To thereaction mixture, 299 mg of sodium triacetoxyborohydride was added, andthe mixture was stirred for 1.5 hours. Thereto was added a saturatedaqueous sodium hydrogen carbonate solution, and the organic layer wasseparated. The organic layer was washed with a saturated aqueous sodiumchloride solution, and dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure. The resultant residuewas purified by silica gel column chromatography using silica gel;Silica Gel 60 made by KANTO CHEMICAL CO., INC., and an eluent ofchloroform:methanol (mixing 5% of 28% ammonium water)=87:13 to obtain275 mg of1-(2-(4-((3-oxo-3,4-dihydro-2H-pyrido(3,2-b)(1,4)oxazin-6-yl)methylamino)piperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-oneas a yellow foam.

To a solution of 260 mg of1-(2-(4-((3-oxo-3,4-dihydro-2H-pyrido(3,2-b)(1,4)oxazin-6-yl)methylamino)piperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-onein 4 mL of ethyl acetate and 2 mL of methanol, 3 mL of 4 mol/L hydrogenchloride/ethyl acetate was added, and the mixture was stirred at roomtemperature for 12 minutes. The solvent was distilled off under reducedpressure, thereto was added diethyl ether, and the solid was filteredoff to obtain 304 mg of 1-(2-(4-((3-oxo-3,4-dihydro-2H-pyrido(3,2-b)(1,4)oxazin-6-yl)methylamino)piperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-onehydrochloride as a white solid.

¹H-NMR (DMSO-d₆) δ: 2.03-2.12 (2H, m), 2.37-2.44 (2H, m), 3.08-3.16 (2H,m), 3.27-3.33 (2H, m), 3.35-3.43 (1H, m), 3.78-3.82 (2H, m), 4.07 (3H,s), 4.19 (2H, t, J=5.5 Hz), 4.70-4.73 (4H, m), 6.72 (1H, d, J=9.6 Hz),7.23 (1H, d, J=8.3 Hz), 7.46 (1H, d, J=8.3 Hz), 7.72 (1H, d, J=2.3 Hz),7.94 (1H, d, J=9.6 Hz), 8.34 (1H, d, J=2.3 Hz), 9.54-9.68 (2H, m),11.30-11.63 (2H, m)

EXAMPLE 80

To a solution of 150 mg of1-(2-(4-(aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-oneand 82 mg of 2,3-dihydro(1,4)dioxino(2,3-b)pyridine-7-carbaldehyde in 15mL of chloroform, 60 mg of acetic acid was added, and the mixture wasstirred at room temperature for 16.5 hours. To the reaction mixture, 158mg of sodium triacetoxyborohydride was added, and the mixture wasstirred for 2 hours. Thereto was added a saturated aqueous sodiumhydrogen carbonate solution, and the organic layer was separated. Theorganic layer was washed with a saturated aqueous sodium chloridesolution and dried over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure. The resultant residue was purifiedby silica gel column chromatography using silica gel; Silica Gel 60Nmade by KANTO CHEMICAL CO., INC., and an eluent ofchloroform:methanol=10:1 to obtain 103 mg of1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-b)pyridin-7-yl)methylamino)piperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-oneas a colorless viscous oily substance.

In a solution of 134 mg of1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-b)pyridin-7-yl)methylamino)piperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-onein 1 mL of methanol and 5 mL of ethyl acetate, 2 mL of 4 mol/L hydrogenchloride/ethyl acetate was added, and the mixture was stirred at roomtemperature. The solid was filtered off to obtain 159 mg of1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-b)pyridin-7-yl)methylamino)piperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-onehydrochloride as a light yellow solid.

¹H-NMR (DMSO-d₆) δ: 2.02-2.11 (2H, m), 2.35-2.42 (2H, m), 3.07-3.17 (2H,m), 3.24-3.32 (3H, m), 3.75-3.82 (2H, m), 4.07 (3H, s), 4.09-4.19 (2H,m), 4.25-4.31 (2H, m), 4.41-4.44 (2H, m), 4.67-4.74 (2H, m), 6.72 (1H,d, J=9.6 Hz), 7.64 (1H, d, J=2.3 Hz), 7.70 (1H, d, J=2.3 Hz), 7.92 (1H,d, J=2.3 Hz), 7.94 (1H, d, J=9.6 Hz), 8.33 (1H, d, J=2.3 Hz), 9.59-9.78(3H, m), 11.26-11.52 (1H, m)

EXAMPLE 81

A solution of 150 mg of1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-yl)methylamino)piperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-oneand 85 mg of bromo acetate in 15 mL of acetonitrile, 100 mg of potassiumcarbonate was added, and the mixture was stirred at room temperature for18 hours, and stirred at 40° C. for 4 hours. The solvent was distilledoff under reduced pressure, thereto were added chloroform and water, andthe organic layer was separated. The organic layer was dried overanhydrous magnesium sulfate, and the solvent was distilled off underreduced pressure. The resultant residue was purified by silica gelcolumn chromatography using silica gel; Silica Gel 60N made by KANTOCHEMICAL CO., INC., and an eluent of chloroform:methanol=20:1 to obtain90 mg of ethyl((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)amino)acetateas an brown oily substance.

¹H-NMR (CDCl₃) δ: 1.26 (3H, m), 1.52-1.60 (2H, m), 1.84-1.89 (2H, m),2.08-2.15 (2H, m), 2.59-2.64 (2H, m), 2.65-2.71 (1H, m), 3.01-3.07 (2H,m), 3.40-3.43 (2H, m), 3.84-3.87 (2H, m), 3.97 (3H, s), 4.12-4.17 (2H,m), 4.26-4.29 (2H, m), 4.31-4.37 (4H, m), 6.72-6.75 (1H, m), 7.13-7.15(1H, m), 7.19-7.21 (1H, m), 7.82-7.85 (1H, m), 8.05-8.07 (1H, m),8.27-8.29 (1H, m)

EXAMPLE 82

A solution of 90 mg of ethyl((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)amino)acetatein 0.2 mL of methanol and 1 mL of tetrahydrofuran, 0.2 mL of a 10%aqueous sodium hydroxide solution was added, and the mixture was stirredat room temperature for 2 hours. The reaction mixture was added with a 1mol/L aqueous hydrochloric acid solution and neutralized, and thesolvent was distilled off under reduced pressure. The resultant residuewas purified by a resin; HP-20, made by Mitsubishi Chemical Corporationand an eluent of acetone to obtain 54 mg of((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)amino)aceticacid as a light yellow solid.

¹H-NMR (DMSO-d₆) δ: 1.26-1.34 (2H, m), 1.66-1.71 (2H, m), 1.74-1.78 (2H,m), 1.90-1.97 (2H, m), 2.94-3.01 (3H, m), 3.58-3.62 (2H, m), 3.66-3.69(2H, m), 3.96 (3H, s), 4.25-4.28 (2H, m), 4.31-4.35 (4H, m), 6.65 (1H,d, J=9.6 Hz), 7.08 (1H, s), 7.40 (1H, d, J=2.3 Hz), 7.86 (1H, d, J=9.6Hz), 7.96 (1H, s), 8.27 (1H, d, J=2.3 Hz)

EXAMPLE 83

To a solution of 75 mg of tert-butyl(1-(2-(7-cyano-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamatein 5 mL of ethyl acetate, 7 mL of a 4 mol/L hydrogen chloride/ethylacetate was added, and the mixture was stirred at room temperature for 2hours. The reaction mixture was alkalified with a saturated aqueoussodium hydrogen carbonate solution, the solvent was distilled off underreduced pressure, and the resultant residue was then purified by silicagel column chromatography using silica gel; Chromatorex-NH made by FujiSilysia Chemical Ltd., and an eluent of chloroform to obtain 34 mg of1-(2-(4-aminopiperidin-1-yl)ethyl)-7-cyano-1,5-naphthyridin-2(1H)-one asa light yellow solid.

To a solution of 32 mg of1-(2-(4-aminopiperidin-1-yl)ethyl)-7-cyano-(1,5-naphthyridin)-2(1H)-oneand 16 mg of 2,3-dihydro(1,4)dioxino(2,3-c)pyridine-7-carbaldehyde in 5mL of chloroform, 9 μL of acetic acid was added, and the mixture wasstirred at room temperature overnight. To the reaction mixture, 34 mg ofsodium triacetoxyborohydride was added, and the mixture was stirred for9 hours. Thereto was added a saturated aqueous sodium hydrogen carbonatesolution, and the solvent was distilled off under reduced pressure. Theresultant residue was purified by silica gel column chromatography usingsilica gel; Chromatorex-NH made by Fuji Silysia Chemical Ltd., and aneluent of chloroform to obtain 39 mg of1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-7-cyano-1,5-naphthyridin-2(1H)-oneas a light yellow solid.

To a solution of 36 mg of 1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-7-cyano-1,5-naphthyridin-2(1H)-onein 5 mL of acetic acid, 0.5 mL of a 4 mol/L hydrogen chloride/ethylacetate and 5 mL of ethyl acetate were added, and the mixture wasstirred at room temperature for 10 minutes. The solvent was distilledoff under reduced pressure to obtain 44 mg of1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-7-cyano-1,5-naphthyridin-2(1H)-onehydrochloride as a white solid.

¹H-NMR (CDCl₃) δ: 2.03-2.09 (2H, m), 2.33-2.38 (2H, m), 3.07-3.15 (2H,m), 3.28-3.36 (3H, m), 3.76-3.81 (2H, m), 4.21-4.24 (2H, m), 4.34-4.36(2H, m), 4.40-4.43 (2H, m), 4.62-4.66 (2H, m), 7.09 (1H, d, J=9.6 Hz),7.26 (1H, s), 8.07 (1H, d, J=9.6 Hz), 8.23 (1H, s), 8.84-8.85 (1H, m),8.96 (1H, d, J=1.8 Hz), 9.65-9.70 (2H, m), 10.74-10.78 (1H, m)

EXAMPLE 84

To a solution of 0.12 g of(3-methoxy-6-oxopyrido(2,3-b)pyrazin-5(6H)-yl)acetaldehyde in 5 mL ofmethylene chloride, 0.18 g of tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(piperidin-4-yl)carbamate,26 μL of acetic acid and 0.12 g of sodium triacetoxyborohydride wereadded, and the mixture was stirred at room temperature for 2 hours 30minutes. To the reaction mixture, a saturated aqueous sodium hydrogencarbonate solution and chloroform were added, the organic layer wasseparated, and the aqueous layer was extracted with chloroform. Theorganic layer and the extract were combined, the resultant solution waswashed with a saturated aqueous sodium chloride solution and dried overanhydrous magnesium sulfate, and the solvent was distilled off underreduced pressure. The resultant residue was purified by silica gelcolumn chromatography using an eluent of chloroform:methanol=20:1 toobtain 0.32 g of tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(3-methoxy-6-oxopyrido(2,3-b)pyrazin-5(6H)-yl)ethyl)piperidin-4-yl)carbamateas a colorless oily substance.

¹H-NMR (CDCl₃) δ: 1.27-1.72 (13H, m), 2.01-2.23 (2H, m), 2.59-2.69 (2H,m), 3.01-3.11 (2H, m), 3.98-4.18 (1H, m), 4.03 (3H, s), 4.19-4.39 (6H,m), 4.46-4.56 (2H, m), 6.71 (1H, s), 6.74 (1H, d, J=9.8 Hz), 7.83 (1H,d, J=9.8 Hz), 8.04 (1H, s), 8.10 (1H, s)

EXAMPLE 85

To 0.32 g of tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(3-methoxy-6-oxopyrido(2,3-b)pyrazin-5(6H)-yl)ethyl)piperidin-4-yl)carbamate,15 mL of a 4 mol/L hydrogen chloride/ethyl acetate solution was added,and the mixture was stirred at room temperature for 2.5 days. Thesolvent was distilled off under reduced pressure, 5 mL of ethyl acetatewas added to the resultant residue, and the solid was filtered off toobtain 0.24 g of5-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl-3-methoxypyrido(2,3-b)pyrazin-6(5H)-onehydrochloride as a yellow solid.

¹H-NMR (D₂O) δ: 1.98-2.13 (2H, m), 2.50-2.59 (2H, m), 3.19-3.35 (2H, m),3.64-3.77 (3H, m), 3.97-4.09 (2H, m), 4.13 (3H, s), 4.45-4.52 (4H, m),4.55-4.61 (2H, m), 4.90-4.94 (1H, m), 6.88 (1H, d, J=9.8 Hz), 7.40 (1H,s), 8.08 (1H, d, J=9.8 Hz), 8.26 (1H, s), 8.33 (1H, s)

EXAMPLE 86

By the same technique as in Example 1, tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(4-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)morpholin-2-ylmethyl)carbamatewas obtained from tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(morpholin-2-ylmethyl)carbamateand (7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde.

¹H-NMR (CDCl₃) δ: 1.35-1.55 (9H, m), 1.95-2.10 (1H, m), 2.23-2.33 (1H,m), 2.58-2.71 (2H, m), 2.75-2.88 (2H, m), 3.17-3.50 (2H, m), 3.53-3.62(1H, m), 3.65-3.79 (1H, m), 3.82-3.89 (1H, m), 3.98 (3H, s), 4.22-4.46(7H, m), 4.52-4.68 (1H, m), 6.69-6.77 (1H, m), 6.74 (1H, d, J=9.6 Hz),7.18 (1H, d, J=2.2 Hz), 7.85 (1H, d, J=9.6 Hz), 8.08 (1H, s), 8.26-8.31(1H, m)

EXAMPLE 87

By the same technique as in Example2,1-(2-(2-(((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)methyl)morpholin-4-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-onehydrochloride was obtained from tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(4-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)morpholin-2-ylmethyl)carbamate.

¹H-NMR (D₂O) δ: 3.11-3.20 (1H, m), 3.27-3.39 (2H, m), 3.43-3.50 (1H, m),3.65-3.74 (2H, m), 3.78-3.86 (1H, m), 3.87-3.97 (2H, m), 4.05 (3H, s),4.21-4.32 (2H, m), 4.44-4.51 (4H, m), 4.56-4.61 (2H, m), 4.70-4.83 (2H,m), 6.89 (1H, d, J=9.8 Hz), 7.42 (1H, s), 7.49-7.53 (1H, m), 8.07 (1H,d, J=9.8 Hz), 8.35 (1H, s), 8.42 (1H, d, J=2.2 Hz)

EXAMPLE 88

By the same technique as in Example 78,1-(2-(4-(((5-fluoro-2-methylpyridin-3-yl)methyl)amino)piperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-onewas obtained from1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-onehydrochloride and 5-fluoro-2-methylnicotinaldehyde.

¹H-NMR (CDCl₃) δ: 1.39-1.51 (2H, m), 1.90-1.99 (2H, m), 2.17-2.28 (2H,m), 2.44-2.61 (1H, m), 2.51 (3H, s), 2.63-2.71 (2H, m), 2.96-3.05 (2H,m), 3.79 (2H, s), 3.98 (3H, s), 4.33-4.42 (2H, m), 6.75 (1H, d, J=9.8Hz), 7.23 (1H, s), 7.47 (1H, dd, J 9.0, 2.6 Hz), 7.85 (1H, d, J=9.8 Hz),8.23 (1H, d, J=2.6 Hz), 8.28 (1H, d, J=2.2 Hz)

EXAMPLE 89

To a suspension of 0.10 g of1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-onehydrochloride in 4 mL of methanol, 31 mg of sodium cyanoborohydridecyanoborohydride, 44 μL of 4-fluoro-3-methylbenzaldehyde, 39 mg of a 28%sodium methoxide/methanol solution and 42 μL of acetic acid were added,and the mixture was stirred at room temperature for 1 hour 15 minutes.Thereto were added 44 μL of 4-fluoro-3-methylbenzaldehyde and 31 mg ofsodium cyanoborohydride cyanoborohydride, and the mixture was stirred atthe same temperature for 45 minutes. Thereto were further added 44 μL of4-fluoro-3-methylbenzaldehyde and 31 mg of sodium cyanoborohydride, andthe mixture was stirred at the same temperature for 30 minutes. Asaturated aqueous sodium hydrogen carbonate solution and ethyl acetatewere added thereto, and the organic layer was separated, washed with asaturated aqueous sodium chloride solution, and dried over anhydrousmagnesium sulfate, and the solvent was distilled off under reducedpressure. The resultant residue was purified by basic silica gel columnchromatography using an eluent of chloroform:methanol=10:1. Theresultant residue was dissolved in 2 mL of ethyl acetate, and theretowas added 1 mL of a 4.0 mol/L hydrogen chloride/ethyl acetate solutionat room temperature. The solvent was distilled off under reducedpressure, ethyl acetate was added to the resultant residue and the solidwas filtered off to obtain 54 mg of1-(2-(4-((4-fluoro-3-methylbenzyl)amino)piperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-onehydrochloride as a light yellow solid.

¹H-NMR (D₂O) δ: 1.95-2.09 (2H, m), 2.28 (3H, d, J=1.5 Hz), 2.47-2.56(2H, m), 3.16-3.26 (2H, m), 3.55-3.64 (3H, m), 3.92-4.00 (2H, m), 4.04(3H, s), 4.27 (2H, s), 4.70-4.90 (2H, m), 6.87 (1H, d, J=9.8 Hz),7.12-7.18 (1H, m), 7.28-7.39 (2H, m), 7.44 (1H, d, J=2.2 Hz), 8.06 (1H,d, J=9.8 Hz), 8.40 (1H, d, J=2.3 Hz)

EXAMPLE 90

By the same technique as in Example 30,6-(((1-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)amino)methyl)-2H-pyrido(3,2-b)(1,4)thiazin-3(4H)-onewas obtained from1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-onehydrochloride and3-oxo-3,4-dihydro-2H-pyrido(3,2-b)(1,4)thiazine-6-carbaldehyde.

¹H-NMR (CDCl₃) δ: 1.40-1.53 (2H, m), 1.87-1.96 (2H, m), 2.14-2.24 (2H,m), 2.47-2.58 (1H, m), 2.62-2.69 (2H, m), 2.95-3.04 (2H, m), 3.48 (2H,s), 3.83 (2H, s), 3.98 (3H, s), 4.33-4.41 (2H, m), 6.74 (1H, d, J=9.6Hz), 6.97 (1H, d, J=7.7 Hz), 7.24 (1H, d, J=2.2 Hz), 7.57 (1H, d, J=7.7Hz), 7.85 (1H, d, J=9.6 Hz), 8.13-8.23 (1H, broad), 8.28 (1H, d, J=2.2Hz)

EXAMPLE 91

To a solution of 0.12 g of(7-(1H-imidazol-1-yl)-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde in 1mL of dichloromethane, a solution of 0.14 g of tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(piperidin-4-yl)carbamatein 1.4 mL of dichloromethane, and 23 μL of acetic acid and 0.13 g ofsodium triacetoxyborohydride were added, and the mixture was stirred atroom temperature for 1 hour 40 minutes. The reaction mixture was chargedwith chloroform, and a saturated aqueous sodium hydrogen carbonatesolution and adjusted to pH 8.6, the organic layer was separated and theaqueous layer was extracted with chloroform. The organic layer and theextract were combined, the resultant solution was washed with water anda saturated aqueous sodium chloride solution and dried over anhydrousmagnesium sulfate, and the solvent was distilled off under reducedpressure. The resultant residue was purified by basic silica gel columnchromatography using gradient elution with chloroform:methanol=19:1 to93:7 to obtain 0.12 g of tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(7-(1H-imidazol-1-yl)-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamateas a light yellow solid.

¹H-NMR (CDCl₃) δ: 1.32-1.72 (13H, m), 2.10-2.27 (2H, m), 2.60-2.69 (2H,m), 2.94-3.03 (2H, m), 4.05-4.15 (1H, m), 4.24-4.40 (8H, m), 6.72 (1H,s), 6.93 (1H, d, J=9.8 Hz), 7.32 (1H, s), 7.39 (1H, s), 7.75 (1H, s),7.93 (1H, d, J=9.8 Hz), 7.97 (1H, s), 8.04 (1H, s), 8.65 (1H, d, J=1.9Hz)

EXAMPLE 92

By the same technique as in Example4,1-(2-(4-(((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-yl)methyl)amino)piperidin-1-yl)ethyl)-7-(1H-imidazol-1-yl)-1,5-naphthyridin-2(1H)-onehydrochloride was obtained from tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(7-(1H-imidazol-1-yl)-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate.

¹H-NMR (D₂O) δ: 1.90-2.15 (2H, m), 2.52-2.61 (2H, m), 3.24-3.36 (2H, m),3.66-3.80 (3H, m), 4.00-4.09 (2H, m), 4.40-4.50 (2H, m), 4.50-4.54 (2H,m), 4.57-4.88 (4H, m), 7.16 (1H, d, J=9.9 Hz), 7.45 (1H, s), 7.77 (1H,t, J=2.0 Hz), 8.09 (1H, t, J=1.6 Hz), 8.19 (1H, d, J=9.9 Hz), 8.36 (1H,s), 8.44 (1H, d, J=1.6 Hz), 8.93 (1H, d, J=2.0 Hz), 9.46 (1H, t, J=1.4Hz)

EXAMPLE 93

By the same technique as in Example 78,1-(2-(4-(((5-fluoro-6-methylpyridin-3-yl)methyl)amino)piperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-onewas obtained from1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-onehydrochloride and 5-fluoro-6-methylnicotinaldehyde.

¹H-NMR (CDCl₃) δ: 1.35-1.47 (2H, m), 1.86-1.95 (2H, m), 2.14-2.24 (2H,m), 2.47-2.56 (1H, m), 2.51 (3H, d, J=2.9 Hz), 2.62-2.68 (2H, m),2.94-3.02 (2H, m), 3.82 (2H, s), 3.98 (3H, s), 4.33-4.40 (2H, m), 6.74(1H, d, J=9.8 Hz), 7.21 (1H, d, J=2.3 Hz), 7.36 (1H, dd, J=9.9, 1.4 Hz),7.84 (1H, d, J=9.8 Hz), 8.23 (1H, s), 8.28 (1H, d, J=2.3 Hz)

EXAMPLE 94

By the same technique as in Example 1, tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)((3R,4R)-3-hydroxy-1-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamatewas obtained from tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)((3R,4R)-3-hydroxypiperidin-4-yl)carbamateand (7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde.

¹H-NMR (CDCl₃) δ: 1.22-1.42 (9H, m), 1.55-1.85 (3H, m), 2.18-2.36 (2H,m), 2.67-2.79 (2H, m), 2.98-3.07 (1H, m), 3.26-3.36 (1H, m), 3.62-3.73(1H, m), 3.94 (3H, s), 4.00-4.52 (8H, m), 6.70-6.84 (2H, m), 7.13-7.17(1H, m), 7.81-8.05 (2H, m), 8.24-8.32 (1H, m)

EXAMPLE 95

To a solution of 75 mg of tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)((3R,4R)-3-hydroxy-1-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamatein 3 mL of ethanol, 3.0 mL of a hydrogen chloride/ethanol solution wasadded at room temperature. The mixture was stirred at the sametemperature for 1 hour, and the solvent was distilled off under reducedpressure. Diethyl ether was added to the resultant residue, and thesolid was filtered off. To the solid, chloroform and water were added,and the aqueous layer was separated. The aqueous layer was charged withchloroform and adjusted to pH 12 with a 1 mol/L aqueous sodium hydroxidesolution. The organic layer was separated, washed with a saturatedaqueous sodium chloride solution and dried over anhydrous magnesiumsulfate, and the solvent was distilled off under reduced pressure toobtain 45 mg of1-(2-((3R,4R)-4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)-3-hydroxypiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-one.

¹H-NMR (CDCl₃) δ: 1.35-1.47 (1H, m), 1.92-2.02 (1H, m), 2.07-2.23 (2H,m), 2.33-2.42 (1H, m), 2.65-2.73 (2H, m), 2.91-2.99 (1H, m), 3.14-3.22(1H, m), 3.44-3.52 (1H, m), 3.72-3.84 (1H, m), 3.92-4.01 (1H, m), 3.97(3H, s), 4.25-4.42 (6H, m), 6.73 (1H, d, J=9.8 Hz), 6.76 (1H, s), 7.18(1H, d, J=2.4 Hz), 7.84 (1H, d, J=9.8 Hz), 8.09 (1H, s), 8.27 (1H, d,J=2.4 Hz)

EXAMPLE 96

By the same technique as in Example 78,5-(2-(4-(((5-fluoro-6-methylpyridin-3-yl)methyl)amino)piperidin-1-yl)ethyl)-3-methoxypyrido(2,3-b)pyrazin-6(5H)-onewas obtained from5-(2-(4-aminopiperidin-1-yl)ethyl)-3-methoxypyrido(2,3-b)pyrazin-6(5H)-onehydrochloride and 5-fluoro-6-methylnicotinaldehyde.

¹H-NMR (CDCl₃) δ: 1.31-1.43 (2H, m), 1.83-1.92 (2H, m), 2.12-2.22 (2H,m), 2.44-2.55 (1H, m), 2.50 (3H, d, J=2.7 Hz), 2.67-2.74 (2H, m),2.99-3.08 (2H, m), 3.81 (2H, s), 4.06 (3H, s), 4.55-4.62 (2H, m), 6.76(1H, d, J=9.8 Hz), 7.36 (1H, d, J=9.8 Hz), 7.84 (1H, d, J=9.8 Hz), 8.11(1H, s), 8.22 (1H, s)

EXAMPLE 97

To a solution of 0.33 g of(2-methoxy-7-oxopyrido(2,3-d)pyrimidin-8(7H)-yl)acetaldehyde in 15 mL ofdichloromethane, a solution of 0.53 g of tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(piperidin-4-yl)carbamatein 5.3 mL of dichloromethane, and 87 μL of acetic acid were added, andthe mixture was stirred at room temperature for 1 hour 30 minutes. Tothe reaction mixture, 0.40 g of sodium triacetoxyborohydride was added,and the mixture was stirred for 2 hours 30 minutes. After leavingovernight, the mixture was stirred at room temperature for 4 hours.Chloroform and a saturated aqueous sodium hydrogen carbonate solutionwere added to the reaction mixture, the organic layer was separated, andthe aqueous layer was extracted with chloroform. The organic layer andthe extract were combined, the resultant solution was washed with asaturated aqueous sodium chloride solution and dried over anhydrousmagnesium sulfate, and the solvent was distilled off under reducedpressure. The resultant residue was purified by silica gel columnchromatography using gradient elution with chloroform:methanol=50:1 to10:1 to obtain 0.55 g of tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(2-methoxy-7-oxopyrido(2,3-d)pyrimidin-8(7H)-yl)ethyl)piperidin-4-yl)carbamateas a light yellow foam.

¹H-NMR (CDCl₃) δ: 1.25-1.69 (13H), 2.01-2.23 (2H, m), 2.61-2.69 (2H, m),3.02-3.11 (2H, m), 3.63-3.84 (1H, m), 4.06 (3H, s), 4.22-4.43 (6H, m),4.45-4.53 (2H, m), 6.57 (1H, d, J=9.4 Hz), 6.71 (1H, s), 7.60 (1H, d,J=9.4 Hz), 8.04 (1H, s), 8.64 (1H, s)

EXAMPLE 98

To a solution of 0.54 g of tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(2-methoxy-7-oxopyrido(2,3-d)pyrimidin-8(7H)-yl)ethyl)piperidin-4-yl)carbamatein 15 mL of dichloromethane, 5 mL of trifluoroacetic acid was added, andthe mixture was stirred at room temperature for 2 hours. A 2 mol/Laqueous sodium hydroxide solution was added under cooling with ice toadjust pH at 13, dichloromethane was added thereto, the organic layerwas separated, and the aqueous layer was extracted with dichloromethane.The organic layer and the extract were combined, the resultant solutionwas washed with a saturated aqueous sodium chloride solution and driedover anhydrous magnesium sulfate, and the solvent was distilled offunder reduced pressure. The resultant residue was purified by basicsilica gel column chromatography using an eluent ofchloroform:methanol=10:1 to obtain 0.34 g of8-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-2-methoxypyrido(2,3-d)pyrimidin-7(8H)-oneas a yellow oily substance.

¹H-NMR (CDCl₃) δ: 1.31-1.43 (2H, m), 1.81-1.90 (2H, m), 2.08-2.19 (2H,m), 2.41-2.55 (1H, m), 2.64-2.72 (2H, m), 2.97-3.06 (2H, m), 3.77 (2H,s), 4.07 (3H, s), 4.23-4.34 (4H, m), 4.50-4.58 (2H, m), 6.56 (1H, d,J=9.5 Hz), 6.80 (1H, s), 7.59 (1H, d, J=9.5 Hz), 8.08 (1H, s), 8.63 (1H,s)

EXAMPLE 99

To a solution of 0.15 g ofN-(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)-2,2,2-trifluoro-N-(piperidin-3-ylmethyl)acetamidein 2 mL of dichloromethane, 85 mg of(7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde and 24 μL ofacetic acid were added, subsequently, 0.13 g of sodiumtriacetoxyborohydride was added, and the mixture was stirred at roomtemperature for 2 hours. To the reaction mixture, chloroform was added,and a saturated aqueous sodium hydrogen carbonate solution was addedthereto under cooling with ice and adjusted to pH 8.0. The organic layerwas separated and the aqueous layer was extracted with chloroform. Theorganic layer and the extract were combined, the resultant solution waswashed with water and a saturated aqueous sodium chloride solution anddried over anhydrous magnesium sulfate, and the solvent was distilledoff under reduced pressure to obtain 0.21 g ofN-(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)-2,2,2-trifluoro-N-(1-(2-(7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-3-ylmethyl)acetamideas a yellow solid. To 0.21 g ofN-(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)-2,2,2-trifluoro-N-(1-(2-(7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-3-ylmethyl)acetamide,3 mL of methanol and 0.7 mL of water were added, and thereto was added62 mg of potassium carbonate. The mixture was stirred at roomtemperature for 1 hour 15 minutes, then stirred at 40 to 50° C. for 1hour, and stirred at 50 to 60° C. for 1 hour 30 minutes. The solvent wasdistilled off under reduced pressure, chloroform and water were added tothe resultant residue, the organic layer was separated, and the aqueouslayer was extracted with chloroform. The organic layer and the extractwere combined, the resultant solution was washed with a saturatedaqueous sodium chloride solution and dried over anhydrous magnesiumsulfate, and the solvent was distilled off under reduced pressure. Theresultant residue was purified by basic silica gel column chromatographyusing gradient elution with hexane:ethyl acetate=92:8 to 88:12 to obtain0.18 g of1-(2-(3-(((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)methyl)piperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-oneas a light yellow oily substance.

¹H-NMR (CDCl₃) δ: 0.90-1.10 (1H, m), 1.45-1.92 (5H, m), 2.05-2.14 (1H,m), 2.46-2.52 (2H, m), 2.60-2.66 (2H, m), 2.85-2.92 (1H, m), 2.98-3.05(1H, m), 3.74 (2H, s), 4.25-4.35 (6H, m), 6.81 (1H, s), 6.86 (1H, d,J=9.8 5 Hz), 7.60 (1H, dd, J=10.4, 2.2 Hz), 7.88 (1H, d, J=9.8 Hz), 8.10(1H, s), 8.41 (1H, d, J=2.4 Hz)

EXAMPLE 100

To a solution of 0.14 g of1-(2-(3-(((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)methyl)piperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-onein 4 mL of ethyl acetate, 1 mL of a 4 mol/L hydrogen chloride/ethylacetate solution was added, and the mixture was stirred at roomtemperature for 20 minutes. The solvent was distilled off under reducedpressure, diethyl ether was added to the resultant residue, and thesolid was filtered off to obtain 0.10 g of1-(2-(3-(((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)methyl)piperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-onehydrochloride as a light yellow solid.

¹H-NMR (D₂O) δ: 1.31-1.48 (1H, m), 1.76-1.90 (1H, m), 2.00-2.14 (2H, m),2.32-2.44 (1H, m), 2.86-3.26 (4H, m), 3.56-4.00 (4H, m), 4.38-4.46 (4H,m), 4.52-4.56 (2H, m), 4.74-4.84 (2H, m), 6.99 (1H, d, J=10.4 Hz), 7.33(1H, s), 7.94 (1H, dd, J=10.4, 2.1 Hz), 8.10 (1H, d, J=10.2 Hz), 8.29(1H, s), 8.56 (1H, d, J=2.1 Hz)

To a suspension of 0.10 g of1-(2-(4-(aminopiperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-onehydrochloride in 2 mL of methanol, 0.15 g of a 28% sodiummethoxide/methanol solution, 39 mg of(5-fluoro-6-methoxy)nicotinaldehyde and 14 μL of acetic acid were added.Thereto was added 31 mg of sodium cyanoborohydride, and the mixture wasstirred at room temperature for 3 hours. After leaving for overnight,the mixture was stirred at room temperature for 35 minutes, 31 mg ofsodium cyanoborohydride was added, and the mixture was stirred at thesame temperature for 1 hour 40 minutes. To the reaction mixture,chloroform and a saturated aqueous sodium hydrogen carbonate solutionwere added, the organic layer was separated, washed with water and asaturated aqueous sodium chloride solution, and dried over anhydrousmagnesium sulfate, and the solvent was distilled off under reducedpressure. The resultant residue was purified by basic silica gel columnchromatography using gradient elution with chloroform:methanol=95:5 to92:8 to obtain 43 mg of7-fluoro-1-(2-(4-(((5-fluoro-6-methoxypyridin-3-yl)methyl)amino)piperidin-1-yl)ethyl)-1,5-naphthyridin-2(1H)-oneas a white solid.

¹H-NMR (CDCl₃) δ: 1.32-1.46 (2H, m), 1.85-1.94 (2H, m), 2.13-2.22 (2H,m), 2.45-2.55 (1H, m), 2.62-2.68 (2H, m), 2.91-2.99 (2H, m), 3.75 (2H,s), 4.01 (3H, m), 4.28-4.34 (2H, m), 6.86 (1H, d, J=9.8 Hz), 7.38 (1H,dd, J=10.9, 2.0 Hz), 7.50-7.55 (1H, m), 7.83 (1H, d, J=2.0 Hz), 7.88(1H, d, J=9.8 Hz), 8.42 (1H, d, 2.4 Hz)

EXAMPLE 102

By the same technique as in Example 78,7-fluoro-1-(2-(4-(((5-fluoro-2,6-dimethylpyridin-3-yl)methyl)amino)piperidin-1-yl)ethyl)-1,5-naphthyridin-2(1H)-onewas obtained from1-(2-(4-aminopiperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-onehydrochloride and 5-fluoro-2,6-dimethylnicotinaldehyde.

¹H-NMR (CDCl₃) δ: 1.36-1.48 (2H, m), 1.87-1.97 (2H, m), 2.16-2.26 (2H,m), 2.42-2.59 (7H, m), 2.62-2.70 (2H, m), 2.92-3.01 (2H, m), 3.74 (2H,s), 4.29-4.37 (2H, m), 6.86 (1H, d, J=9.5 Hz), 7.34 (1H, d, J=10.0 Hz),7.54 (1H, dd, J=10.2, 2.0 Hz), 7.89 (1H, d, J=10.0 Hz), 8.42 (1H, d,J=2.2 Hz)

EXAMPLE 103

To a suspension of 0.10 g of1-(2-(4-aminopiperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-onehydrochloride and 61 mg of3,4-dihydro-2H-pyrano(2,3-c)pyridine-6-carbaldehyde in 2.5 mL ofmethanol, 62 mg of sodium cyanoborohydride, 0.14 g of a 28% sodiummethoxide/methanol solution and 86 μL of acetic acid were added, and themixture was stirred at room temperature for 1 hour 50 minutes. Theretowere added ethyl acetate, a saturated aqueous sodium hydrogen carbonatesolution, and a 2 mol/L aqueous sodium hydroxide solution, the organiclayer was separated, and the aqueous layer was extracted with ethylacetate twice. The organic layer and the extract were combined, theresultant solution was washed with a saturated aqueous sodium chloridesolution and dried over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure. The resultant residue was purifiedby basic silica gel column chromatography using an eluent ofchloroform:methanol=10:1. The resultant residue was dissolved in 1 mL ofmethanol and 1 mL of and ethyl acetate, and thereto was added 0.5 mL ofa 4 mol/L hydrogen chloride/ethyl acetate solution at room temperature.The solvent was distilled off under reduced pressure, diethyl ether wasadded the resultant residue, and the solid was filtered off to obtain0.11 g of1-(2-(4-((3,4-dihydro-2H-pyrano(2,3-c)pyridin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-onehydrochloride as a light yellow solid.

¹H-NMR (D₂O) δ: 2.00-2.12 (4H, m), 2.50-2.59 (2H, m), 2.93 (2H, t, J=6.3Hz), 3.22-3.32 (2H, m), 3.60-3.75 (1H, m), 3.63 (2H, t, J=5.9 Hz),3.95-4.06 (2H, m), 4.33-4.36 (2H, m), 4.44 (2H, s), 4.72-4.92 (2H, m),6.99 (1H, d, J=9.9 Hz), 7.52 (1H, s), 7.95 (1H, dd, J=10.3, 2.1 Hz),8.10 (1H, d, J=9.9 Hz), 8.20 (1H, s), 8.57 (1H, d, J=2.1 Hz)

EXAMPLE 104

To a solution of 62 mg of(3S)—N-(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)pyrrolidin-3-aminehydrochloride in 3 mL of methanol, 0.10 g of a 28% sodiummethoxide/methanol solution, 37 mg of(7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde, 60 μL of aceticacid, 0.12 g of molecular sieves 3 A and 11 mg of sodiumcyanoborohydride were added at room temperature, and the mixture wasstirred at the same temperature for 1 hour 10 minutes. To the reactionmixture, a saturated aqueous sodium hydrogen carbonate solution andethyl acetate were added, the organic layer was separated, and theaqueous layer was extracted with ethyl acetate. The organic layer andthe extract were combined, the resultant solution was washed with asaturated aqueous sodium chloride solution and dried over anhydrousmagnesium sulfate, and the solvent was distilled off under reducedpressure. The resultant residue was purified by basic silica gel columnchromatography using an eluent of chloroform:methanol=30:1, thereto wereadded ethyl acetate and a 4 mol/L hydrogen chloride/ethyl acetatesolution, and the solid was filtered off to obtain 33 mg of1-(2-((3S)-3-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)pyrrolidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-onehydrochloride as a yellow solid.

¹H-NMR (D₂O) δ: 2.16-2.34 (1H, m), 2.55-2.70 (1H, m), 3.35-3.95 (6H, m),4.16-4.26 (1H, m), 4.45-4.85 (8H, m), 6.98 (1H, d, J=10.0 Hz), 7.47 (1H,s), 7.94-7.98 (1H, m), 8.08 (1H, d, J=10.0 Hz), 8.36 (1H, s), 8.56 (1H,s)

EXAMPLE 105

By the same technique as in Example 78,7-fluoro-1-(2-(4-(((5-fluoro-6-methylpyridin-3-yl)methyl)amino)piperidin-1-yl)ethyl)-1,5-naphthyridin-2(1H)-onewas obtained from1-(2-(4-aminopiperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-onehydrochloride and 5-fluoro-6-methylnicotinaldehyde.

¹H-NMR (CDCl₃) δ: 1.33-1.45 (2H, m), 1.85-1.94 (2H, m), 2.14-2.23 (2H,m), 2.46-2.55 (1H, m), 2.51 (3H, d, J=2.7 Hz), 2.61-2.68 (2H, m),2.91-3.00 (2H, m), 3.81 (2H, s), 4.28-4.35 (2H, m), 6.86 (1H, d, J=9.8Hz), 7.36 (1H, dd, J=10.1, 1.6 Hz), 7.53 (1H, dd, J=10.2, 2.3 Hz), 7.88(1H, d, J=9.8 Hz), 8.23 (1H, s), 8.42 (1H, d, J=2.3 Hz)

EXAMPLE 106

By the same technique as in Example 1, tert-butyl(3,4-dihydro-2H-(1,4)dioxepino(2,3-c)pyridin-8-ylmethyl)(1-(2-(7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamatewas obtained from tert-butyl(3,4-dihydro-2H-(1,4)dioxepino(2,3-c)pyridin-8-ylmethyl)(piperidin-4-yl)carbamateand (7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde.

¹H-NMR (CDCl₃) δ: 1.28-1.74 (13H, m), 2.07-2.30 (4H, m), 2.57-2.65 (2H,m), 2.94-3.03 (2H, m), 4.06-4.18 (1H, m), 4.20-4.40 (8H, m), 6.77 (1H,s), 6.85 (1H, d, J=9.8 Hz), 7.47 (1H, dd, J=10.4, 2.3 Hz), 7.87 (1H, d,J=9.8 Hz), 8.14 (1H, s), 8.41 (1H, d, J=2.3 Hz)

EXAMPLE 107

By the same technique as in Example2,1-(2-(4-((3,4-dihydro-2H-(1,4)dioxepino(2,3-c)pyridin-8-ylmethyl)amino)piperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-onehydrochloride was obtained from tert-butyl(3,4-dihydro-2H-(1,4)dioxepino(2,3-c)pyridin-8-ylmethyl)(1-(2-(7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate.

¹H-NMR (D₂O) δ: 2.00-2.15 (2H, m), 2.37 (2H, quint, J=5.9 Hz), 2.51-2.60(2H, m), 3.20-3.35 (2H, m), 3.60-3.78 (3H, m), 3.97-4.07 (2H, m), 4.42(2H, t, J=5.9 Hz), 4.48 (2H, s), 4.60 (2H, t, J=5.9 Hz), 4.71-4.87 (2H,m), 6.99 (1H, d, J=10.0 Hz), 7.37 (1H, s), 7.96 (1H, dd, J=10.1, 2.1Hz), 8.10 (1H, d, J=10.0 Hz), 8.37 (1H, s), 8.57 (1H, d, J=2.1 Hz)

EXAMPLE 108

By the same technique as in Example 30,1-(2-(4-(((1,3)dioxolo(4,5-c)pyridin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-onewas obtained from1-(2-(4-aminopiperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-onehydrochloride and (1,3)dioxolo(4,5-c)pyridine-6-carbaldehyde.

¹H-NMR (CDCl₃) δ: 1.36-1.50 (2H, m), 1.80-1.97 (2H, m), 2.13-2.24 (2H,m), 2.47-2.57 (1H, m), 2.61-2.68 (2H, m), 2.91-3.00 (2H, m), 3.83 (2H,s), 4.28-4.36 (2H, m), 6.03 (2H, s), 6.86 (1H, d, J=9.8 Hz), 6.88 (1H,s), 7.56 (1H, dd, J=10.2, 2.1 Hz), 7.88 (1H, dd, J=9.8, 0.5 Hz), 8.00(1H, s), 8.41 (1H, d, J=2.1 Hz)

EXAMPLE 109

By the same technique as in Example8,1-(2-(4-(((1,3)dioxolo(4,5-c)pyridin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-onehydrochloride was obtained from1-(2-(4-((((1,3)dioxolo(4,5-c)pyridin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one.

¹H-NMR (D₂O) δ: 2.00-2.14 (2H, m), 2.50-2.60 (2H, m), 3.20-3.35 (2H, m),3.60-3.78 (3H, m), 3.96-4.07 (2H, m), 4.48 (2H, s), 4.70-4.88 (2H, m),6.34 (2H, s), 7.00 (1H, d, J=9.9 Hz), 7.32 (1H, s), 7.93-7.99 (1H, m),8.10 (1H, d, J=9.9 Hz), 8.16 (1H, s), 8.57 (1H, d, J=2.2 Hz)

EXAMPLE 110

To 0.12 g of tert-butyl((5-(1,3-dioxolan-2-yl)methyl)-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)(methyl)carbamate,2 mL of an 80% aqueous trifluoroacetic acid solution was added, and themixture was stirred at room temperature for 2 hours. After leavingovernight, 2 mL of an 80% aqueous trifluoroacetic acid solution wasadded thereto, and the mixture was stirred at room temperature for 1hour 30 minutes, and stirred at 40 to 50° C. for 35 minutes. Thereaction mixture was charged with a 20% aqueous sodium hydroxidesolution and chloroform and adjusted to pH 6.3. The organic layer wasseparated, and the aqueous layer was extracted with chloroform. Further,while keeping the aqueous layer around neutral, the aqueous layer wasextracted with a mixed solvent of chloroform:methanol (5:95). Theorganic layer and the extract were combined, the resultant solution wasdried over anhydrous magnesium sulfate, and the solvent was distilledoff under reduced pressure to obtain 76 mg of(7-(methylamino)-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde as ayellow solid.

To 76 mg of(7-(methylamino)-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde, asolution of 0.11 g of tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(piperidin-4-yl)carbamatein 2.5 mL of dichloromethane and 19 μL of acetic acid were added, andthe mixture was stirred at room temperature for 5 minutes. To thereaction mixture, 0.10 g of sodium triacetoxyborohydride was added, andthe mixture was stirred at the same temperature for 2 hours 20 minutes.Thereto was added chloroform and the reaction mixture was adjusted to pH8.3 with a saturated aqueous sodium hydrogen carbonate solution. Theorganic layer was separated, and the aqueous layer was extracted withchloroform. The organic layer and the extract were combined, theresultant solution was washed with water and a saturated aqueous sodiumchloride solution and dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure. The resultant residuewas purified by basic silica gel column chromatography using an eluentof chloroform:methanol=19:1 to obtain 55 mg of tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(7-(methylamino)-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamateas a light yellow oily substance.

¹H-NMR (CDCl₃) δ: 1.34-1.73 (13H, m), 2.10-2.26 (2H, m), 2.58-2.64 (2H,m), 2.96 (3H, d, J=5.1 Hz), 2.98-3.05 (2H, m), 4.03-4.17 (1H, m),4.25-4.45 (8H, m), 6.57 (1H, d, J=9.8 Hz), 6.70-6.76 (2H, m), 7.74 (1H,d, J=9.8 Hz), 7.98 (1H, d, J=2.2 Hz), 8.05 (1H, s)

EXAMPLE 111

By the same technique as in Example4,1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-7-(methylamino)-1,5-naphthyridin-2(1H)-onehydrochloride was obtained from tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(7-(methylamino)-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate.

¹H-NMR (D₂O) δ: 1.96-2.12 (2H, m), 2.48-2.57 (2H, m), 2.95 (3H, s),3.20-3.32 (2H, m), 3.60-3.72 (3H, m), 3.95-4.04 (2H, m), 4.37-4.44 (4H,m), 4.47-4.52 (2H, m), 4.77-4.83 (2H, m), 6.75 (1H, d, J=9.8 Hz),7.05-7.08 (1H, m), 7.23 (1H, s), 7.97 (1H, d, J=9.8 Hz), 8.16 (1H, d,J=2.2 Hz), 8.24 (1H, s)

EXAMPLE 112

By the same technique as in Example 78, tert-butyl7-(((1-(2-(7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)amino)methyl)-2,3-dihydro-4H-pyrido(4,3-b)(1,4)oxazine-4-carboxylatewas obtained from1-(2-(4-aminopiperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-onehydrochloride and tert-butyl7-formyl-2,3-dihydro-4H-pyrido(4,3-b)(1,4)oxazine-4-carboxylate.

¹H-NMR (CDCl₃) δ: 1.38-1.49 (2H, m), 1.59 (9H, s), 1.87-1.95 (2H, m),2.13-2.23 (2H, m), 2.48-2.57 (1H, m), 2.61-2.66 (2H, m), 2.92-2.98 (2H,m), 3.81 (2H, s), 3.84-3.87 (2H, m), 4.28-4.34 (4H, m), 6.82 (1H, s),6.86 (1H, d, J=9.9 Hz), 7.55 (1H, dd, J=10.5, 2.2 Hz), 7.88 (1H, d,J=9.9 Hz), 8.41 (1H, d, J=2.2 Hz), 8.79-8.87 (1H, m)

EXAMPLE 113

By the same technique as in Example2,1-(2-(4-((3,4-dihydro-2H-pyrido(4,3-b)(1,4)oxazin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-onehydrochloride was obtained from tert-butyl7-(((1-(2-(7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)amino)methyl)-2,3-dihydro-4H-pyrido(4,3-b)(1,4)oxazine-4-carboxylate.

¹H-NMR (D₂O) δ: 2.00-2.12 (2H, m), 2.52-2.60 (2H, m), 3.23-3.36 (2H, m),3.51 (2H, t, J=4.4 Hz), 3.64 (2H, t, J=6.0 Hz), 3.68-3.78 (1H, m),3.98-4.06 (2H, m), 4.48-4.54 (4H, m), 4.66-4.92 (2H, m), 6.99 (1H, d,J=9.8 Hz), 7.30-7.36 (1H, m), 7.92-7.98 (1H, m), 8.01 (1H, s), 8.11 (1H,d, J=9.8 Hz), 8.57 (1H, s)

EXAMPLE 114

To a solution of 40 mg of1-(2-(1-hydroxy-4-oxocyclohexyl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-onein 5 mL of dichloromethane, 25 mg of1-(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-yl)methanamine and 11 μL ofacetic acid were added at room temperature, the mixture was stirred for2 hours, then, 27 mg of sodium triacetoxyborohydride was added to thereaction mixture, and the mixture was stirred at room temperature for 1hour. Thereto were added a saturated aqueous sodium hydrogen carbonatesolution and chloroform, the organic layer was separated, and washedwith a saturated aqueous sodium chloride solution and dried overanhydrous magnesium sulfate, and the solvent was distilled off underreduced pressure. The resultant residue was purified by basic silica gelcolumn chromatography using an eluent of chloroform:methanol=30:1 toobtain 10 mg of(A)1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)-1-hydroxycyclohexyl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-oneas a light yellow solid and 9 mg of (B)1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)-1-hydroxycyclohexyl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-oneas a light yellow solid.

(A) ¹H-NMR (CDCl₃) δ: 1.35-1.55 (4H, m), 1.80-2.20 (6H, m), 2.65-2.75(1H, m), 3.77 (2H, s), 3.97 (3H, s), 4.25-4.46 (6H, m), 6.75 (1H, d,J=9.6 Hz), 6.80 (1H, s), 7.32 (1H, d, J=2.4 Hz), 7.86 (1H, d, J=9.6 Hz),8.10 (1H, s), 8.29 (1H, d, J=2.4 Hz) (B) ¹H-NMR (CDCl₃) δ: 1.40-1.60(4H, m), 1.70-1.90 (6H, m), 2.48-2.58 (1H, m), 3.82 (2H, s), 3.96 (3H,s), 4.26-4.44 (6H, m), 6.74 (1H, d, J=9.6 Hz), 6.82 (1H, s), 7.38 (1H,d, J=2.4 Hz), 7.85 (1H, d, J=9.6 Hz), 8.11 (1H, s), 8.28 (1H, d, J=2.4Hz)

EXAMPLE 115

By the same technique as in Example 3, tert-butyl1-(2-(7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)(3-(pyrazin-2-yl)-2-propyn-1-yl)carbamatewas obtained from7-fluoro-1-(2-hydroxy-2-methoxyethyl)-1,5-naphthyridin-2(1H)-one andtert-butyl (piperidin-4-yl)(3-(pyrazin-2-yl)-2-propyn-1-yl)carbamate.

¹H-NMR (CDCl₃) δ: 1.50 (9H, s), 1.78-1.88 (4H, m), 2.16-2.28 (2H, m),2.66 (2H, t, J=7.1 Hz), 3.03-3.12 (2H, m), 4.04-4.25 (3H, m), 4.32 (2H,t, J=7.1 Hz), 6.86 (1H, d, J=9.8 Hz), 7.48-7.54 (1H, m), 7.88 (1H, d,J=9.8 Hz), 8.41 (1H, d, J=2.4 Hz), 8.48 (1H, d, J=2.7 Hz), 8.51-8.54(1H, m), 8.62 (1H, d, J=1.2 Hz)

EXAMPLE 116

To a solution of 96 mg of tert-butyl1-(2-(7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)(3-(pyrazin-2-yl)-2-propyn-1-yl)carbamatein 2 mL of chloroform, 1 mL of trifluoroacetic acid was added at roomtemperature, and the mixture was stirred for 1 hour 30 minutes. Theretowas added a saturated aqueous sodium hydrogen carbonate solution, theorganic layer was separated, and the aqueous layer was extracted withchloroform. The organic layer and the extract were combined, theresultant solution was dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure. The resultant residuewas purified by basic silica gel column chromatography using an eluentof chloroform:methanol 20:1 to obtain 20 mg of7-fluoro-1-(2-(4-((3-(pyrazin-2-yl)prop-2-in-1-yl)amino)piperidin-1-yl)ethyl)-1,5-naphthyridin-2(1H)-oneas a yellow oily substance.

¹H-NMR (CDCl₃) δ: 1.38-1.49 (2H, m), 1.86-1.95 (2H, m), 2.21-2.30 (2H,m), 2.67 (2H, t, J=7.1 Hz), 2.76-2.86 (1H, m), 2.93-3.01 (2H, m), 3.76(2H, s), 4.33 (2H, t, J=7.1 Hz), 6.86 (1H, d, J=9.8 Hz), 7.56 (1H, dd, J10.3, 2.2 Hz), 7.89 (1H, d, J=9.8 Hz), 8.42 (1H, d, J=2.2 Hz), 8.48 (1H,d, J=2.4 Hz), 8.52-8.55 (1H, m), 8.65 (1H, d, J=1.4 Hz)

EXAMPLE 117

To 85 mg of1-(2-(4-((3,4-dihydro-2H-(1,4)dioxepino(2,3-c)pyridin-8-ylmethyl)amino)piperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-onehydrochloride, chloroform and a saturated aqueous sodium hydrogencarbonate solution were added, the organic layer was separated, and theaqueous layer was extracted with chloroform. The organic layer and theextract were combined, the resultant solution was washed with asaturated aqueous sodium chloride solution and dried over anhydrousmagnesium sulfate, and the solvent was distilled off under reducedpressure. To the resultant oily substance, 2 mL of methanol and 83 mg ofa 28% sodium methoxide/methanol solution were added at room temperature,and the mixture was heated under reflux while stirring for 4 hours.After cooling to room temperature, water and chloroform were added tothe reaction mixture, the organic layer was separated, and the aqueouslayer was extracted with chloroform. The organic layer and the extractwere combined, the resultant residue was washed with a saturated aqueoussodium chloride solution and dried over anhydrous magnesium sulfate, andthe solvent was distilled off under reduced pressure to obtain 53 mg of1-(2-(4-((3,4-dihydro-2H-(1,4)dioxepino(2,3-c)pyridin-8-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-oneas a light brown oily substance.

¹H-NMR (CDCl₃) δ: 1.38-1.52 (2H, m), 1.86-1.97 (2H, m), 2.13-2.28 (4H,m), 2.46-2.59 (1H, m), 2.61-2.68 (2H, m), 2.94-3.02 (2H, m), 3.78-3.84(2H, m), 3.97 (3H, s), 4.24 (2H, t, J=5.8 Hz), 4.31-4.40 (4H, m), 6.74(1H, d, J=9.8 Hz), 6.86 (1H, s), 7.23-7.32 (1H, m), 7.84 (1H, d, J=9.8Hz), 8.18 (1H, s), 8.27 (1H, d, J=2.4 Hz)

EXAMPLE 118

By the same technique as in Example8,1-(2-(4-((3,4-dihydro-2H-(1,4)dioxepino(2,3-c)pyridin-8-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-onehydrochloride was obtained from1-(2-(4-((3,4-dihydro-2H-(1,4)dioxepino(2,3-c)pyridin-8-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-one.

¹H-NMR (D₂O) δ: 1.99-2.14 (2H, m), 2.35 (2H, quint, J=5.9 Hz), 2.50-2.60(2H, m), 3.20-3.34 (2H, m), 3.60-3.76 (3H, m), 3.96-4.07 (2H, m), 4.06(3H, s), 4.40 (2H, t, J=5.9 Hz), 4.44 (2H, s), 4.56 (2H, t, J=5.9 Hz),4.71-4.87 (2H, m), 6.90 (1H, d, J=9.8 Hz), 7.31 (1H, s), 7.53 (1H, d,J=2.1 Hz), 8.07 (1H, d, J=9.8 Hz), 8.34 (1H, s), 8.43 (1H, d, J=2.1 Hz)

EXAMPLE 119

By the same technique as in Example 114, (A)5-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)-1-hydroxycyclohexyl)ethyl)-3-methoxypyrido(2,3-b)pyrazin-6(5H)-oneas a yellow oily substance and (B)5-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)-1-hydroxycyclohexyl)ethyl)-3-methoxypyrido(2,3-b)pyrazin-6(5H)-oneas a light yellow solid were obtained from5-(2-(1-hydroxy-4-oxocyclohexyl)ethyl)-3-methoxypyrido(2,3-b)pyrazin-6(5H)-oneand 1-(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-yl)methanamine.

(A) ¹H-NMR (CDCl₃) δ: 1.33-1.56 (4H, m), 1.70-1.95 (4H, m), 1.99 (2H, t,J=7.3 Hz), 2.62-2.71 (1H, m), 3.75 (2H, s), 4.08 (3H, s), 4.25-4.35 (4H,m), 4.59 (2H, t, J=7.3 Hz), 6.77 (1H, d, J=9.6 Hz), 6.78 (1H, s), 7.86(1H, d, J=9.6 Hz), 8.10 (1H, s), 8.13 (1H, s) (B) ¹H-NMR (CDCl₃) δ:1.38-1.48 (2H, m), 1.50-1.90 (8H, m), 2.42-2.54 (1H, m), 3.82 (2H, s),4.08 (3H, s), 4.24-4.35 (4H, m), 4.57-4.62 (2H, m), 6.77 (1H, d, J=10.0Hz), 6.83 (1H, s), 7.85 (1H, d, J=10.0 Hz), 8.10 (1H, s), 8.13 (1H, s)

EXAMPLE 120

To a suspension of 0.10 g of1-(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-yl)-N-(pyrrolidin-3-ylmethyl)methanaminehydrochloride in 5 mL of methanol, 0.17 g of a 28% sodiummethoxide/methanol solution, 66 mg of(7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde, 0.10 g ofmolecular sieves 3 A, 33 μL of acetic acid and 18 mg of sodiumcyanoborohydride were added at room temperature, and the mixture wasstirred at the same temperature for 2 hours 30 minutes. To the reactionmixture, a saturated aqueous sodium hydrogen carbonate solution andethyl acetate were added, the organic layer was separated, and theaqueous layer was extracted with ethyl acetate. The organic layer andthe extract were combined, the resultant solution was washed with asaturated aqueous sodium chloride solution and dried over anhydrousmagnesium sulfate, and the solvent was distilled off under reducedpressure. The resultant residue was purified by basic silica gel columnchromatography using an eluent of chloroform:methanol=30:1 to obtain 20mg of1-(2-(3-(((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)methyl)pyrrolidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-oneas a yellow oily substance.

¹H-NMR (CDCl₃) δ: 1.45-1.55 (1H, m), 1.96-2.07 (1H, m), 2.32-2.47 (2H,m), 2.59-2.88 (7H, m), 3.77 (2H, s), 4.25-4.37 (6H, m), 6.81 (1H, s),6.86 (1H, d, J=9.8 Hz), 7.54 (1H, dd, J=10.2, 2.1 Hz), 7.88 (1H, d,J=9.8 Hz), 8.10 (1H, s), 8.41 (1H, d, J=2.1 Hz)

EXAMPLE 121

By the same technique as in Example 55,7-methoxy-1-(2-(4-(((6-oxido-2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-yl)methyl)amino)piperidin-1-yl)ethyl)-1,5-naphthyridin-2(1H)-onewas obtained from1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-onehydrochloride and 2,3-dihydro(1,4)dioxino(2,3-c)pyridine-7-carbaldehyde6-oxide.

¹H-NMR (CDCl₃) δ: 1.38-1.50 (2H, m), 1.85-1.96 (2H, m), 2.13-2.23 (2H,m), 2.44-2.54 (1H, m), 2.61-2.68 (2H, m), 2.93-3.02 (2H, m), 3.93 (2H,s), 3.98 (3H, s), 4.28-4.40 (6H, m), 6.74 (1H, d, J=9.8 Hz), 6.94 (1H,s), 7.23 (1H, d, J=2.2 Hz), 7.84 (1H, d, J=9.8 Hz), 7.97 (1H, s), 8.28(1H, d, J=2.2 Hz)

EXAMPLE 122

To a suspension of 0.20 g of1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-onehydrochloride in 2 mL of methanol, 0.28 g of a 28% sodiummethoxide/methanol solution, 66 mg of 5-ethylpyridine-2-carbaldehyde and28 μL of acetic acid were added. Then, 61 mg of sodium cyanoborohydridewas added thereto and the mixture was stirred at room temperature for 3hours. Thereto was further added 31 mg of sodium cyanoborohydride, andthe mixture was stirred at room temperature for 1 hour 30 minutes. Tothe reaction mixture, chloroform and a saturated aqueous sodium hydrogencarbonate solution were added. The organic layer was separated, washedwith water and a saturated aqueous sodium chloride solution and driedover anhydrous magnesium sulfate, and the solvent was distilled offunder reduced pressure. The resultant residue was purified by basicsilica gel column chromatography using gradient elution withchloroform:methanol=93:7 to 9:1 to obtain 0.15 g of1-(2-(4-(((5-ethylpyridin-2-yl)methyl)amino)piperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-oneas a light yellow oily substance.

¹H-NMR (CDCl₃) δ: 1.24 (3H, t, J=6.6 Hz), 1.40-1.52 (2H, m), 1.89-1.97(2H, m), 2.15-2.23 (2H, m), 2.50-2.59 (1H, m), 2.60-2.67 (4H, m),2.95-3.02 (2H, m), 3.90 (2H, s), 3.97 (3H, s), 4.34-4.39 (2H, m), 6.74(1H, d, J=9.6 Hz), 7.21 (1H, d, J=7.9 Hz), 7.25 (1H, d, J=2.2 Hz), 7.47(1H, dd, J=7.9, 2.4 Hz), 7.84 (1H, d, J=9.7 Hz), 8.27 (1H, d, J=2.4 Hz),8.39 (1H, d, J=2.2 Hz)

EXAMPLE 123

By the same technique as in Example 100,1-(2-(4-(((5-ethylpyridin-2-yl)methyl)amino)piperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-onehydrochloride was obtained from1-(2-(4-(((5-ethylpyridin-2-yl)methyl)amino)piperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-one.

¹H-NMR (D₂O) δ: 1.28 (3H, t, J=7.6 Hz), 2.02-2.17 (2H, m), 2.53-2.62(2H, m), 2.83 (2H, t, J=7.6 Hz), 3.22-3.35 (2H, m), 3.62-3.82 (3H, m),3.98-4.10 (2H, m), 4.06 (3H, s), 4.61 (2H, s), 4.70-4.92 (2H, m), 6.92(1H, d, J=9.9 Hz), 7.56 (1H, d, J=2.1 Hz), 7.84 (1H, d, J=8.2 Hz), 8.08(1H, d, J=9.9 Hz), 8.24 (1H, dd, J=8.2, 1.5 Hz), 8.44 (1H, d, J=2.1 Hz),8.65 (1H, d, J=1.5 Hz)

EXAMPLE 124

To a solution of 50 mg of 3-fluoro-4-methylbenzoic acid in 0.64 mL ofthionyl chloride, 50 μL of N,N-dimethylformamide was added, and themixture was heated under reflux while stirring for 1 hour. The solventwas distilled off under reduced pressure, and the mixture was dissolvedin 4.0 mL of dichloromethane, thereto were added 0.13 mL oftriethylamine and 64 mg of1-(2-(4-aminopiperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-onehydrochloride under cooling with ice, and the mixture was stirred for 2hours. Thereto were added chloroform and water, and the mixture wasadjusted to pH 1 with 6 mol/L hydrochloric acid. The solid was filteredoff to obtain 51 mg of3-fluoro-N-(1-(2-(7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)-4-methylbenzamidehydrochloride as a white solid.

¹H-NMR (DMSO-d₆) δ: 1.83-1.96 (2H, m), 2.00-2.11 (2H, m), 2.29 (3H, s),3.00-3.50 (4H, m), 3.70-3.79 (2H, m), 3.99-4.11 (1H, m), 4.58-4.66 (2H,m), 6.90 (1H, d, J=9.9 Hz), 7.37-7.42 (1H, m), 7.62-7.68 (2H, m), 8.02(1H, d, J=9.9 Hz), 8.27-8.36 (1H, m), 8.52-8.57 (1H, m), 8.61-8.65 (1H,m), 9.95-10.07 (1H, m)

EXAMPLE 125

To a solution of 50 mg of2,3-dihydro(1,4)dioxino(2,3-c)pyridine-7-carboxylic acid in 2.0 mL ofthionyl chloride, one drop of N,N-dimethylformamide was added, and themixture was heated under reflux while stirring for 1 hour 30 minutes.The solvent was distilled off under reduced pressure, the mixture wasdissolved in 2.0 mL of dichloromethane, and 0.14 mL of triethylamine and53 mg of1-(2-(4-aminopiperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-onehydrochloride were added thereto, and the mixture was stirred for 1hour. Chloroform and water were added, the organic layer was separated,and the aqueous layer was extracted with chloroform. The organic layerand the extract were combined, the resultant solution was washed with anaqueous sodium hydroxide solution and then with a saturated aqueoussodium chloride solution, and dried over anhydrous magnesium sulfate,and the solvent was distilled off under reduced pressure. To theresultant residue, a mixed solvent of ethyl acetate:diethyl ether wasadded to obtain 48 mg ofN-(1-(2-(7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)-2,3-dihydro(1,4)dioxino(2,3-c)pyridine-7-carboxamideas a light brown solid.

¹H-NMR (CDCl₃) δ: 1.50-3.20 (10H, m), 3.94-4.13 (1H, m), 4.30-4.40 (6H,m), 6.86 (1H, d, J=9.9 Hz), 7.70 (1H, s), 7.77-7.95 (1H, m), 7.91 (1H,d, J=9.9 Hz), 8.07 (1H, s), 8.43 (1H, d, J=2.2 Hz)

EXAMPLE 126

To a solution of 0.14 g of(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde in 12 mL ofdichloromethane, 0.23 g of tert-butyl((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)methyl)(piperidin-4-yl)carbamateand 37 μL of acetic acid were added, and the mixture was stirred at roomtemperature for 30 minutes. Then, 0.17 g of sodium triacetoxyborohydridewas added to the reaction mixture, and after stirring at roomtemperature for 30 minutes, the mixture was left overnight and furtherstirred for 5 hours. To the reaction mixture, water, a saturated aqueoussodium hydrogen carbonate solution and chloroform were added, theorganic layer was separated, and the aqueous layer was extracted withchloroform. The organic layer and the extract were combined, theresultant solution was washed with a saturated aqueous sodium chloridesolution and dried over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure. The resultant residue was purifiedby silica gel column chromatography using an eluent ofchloroform:methanol=50:1 to obtain 0.23 g of tert-butyl1-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)methyl)carbamateas a light yellow foam.

¹H-NMR (CDCl₃) δ: 1.28-1.88 (13H, m), 2.10-2.28 (2H, m), 2.58-2.72 (4H,m), 2.87-3.09 (4H, m), 3.97 (3H, s), 4.06-4.23 (1H, m), 4.27-4.47 (4H,m), 6.73 (1H, d, J=9.6 Hz), 6.80-6.91 (1H, m), 7.18 (1H, s), 7.42 (1H,d, J=7.3 Hz), 7.84 (1H, d, J=9.6 Hz), 8.21 (1H, s), 8.28 (1H, d, J=2.2Hz)

EXAMPLE 127

By the same technique as in Example 2,7-methoxy-1-(2-(4-(((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)methyl)amino)piperidin-1-yl)ethyl)-1,5-naphthyridin-2(1H)-onehydrochloride was obtained from tert-butyl1-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)methyl)carbamate.

¹H-NMR (D₂O) δ: 2.01-2.21 (2H, m), 2.48-2.63 (2H, m), 2.65-2.75 (2H, m),2.97-3.07 (2H, m), 3.19-3.41 (2H, m), 3.59-3.77 (3H, m), 3.97-4.11 (2H,m), 4.09 (3H, s) 4.40 (2H, s), 4.52-5.18 (2H, m), 6.95 (1H, d, J=9.5Hz), 7.15 (1H, d, J=7.4 Hz), 7.66 (1H, s), 7.72 (1H, d, J=7.4 Hz), 8.07(1H, d, J=9.5 Hz), 8.46 (1H, s)

EXAMPLE 128

To a solution of 71 mg of 4-methoxy-5-methylpyridine-2-carbaldehyde in 2mL of methanol, 0.27 g of a 28% sodium methoxide/methanol solution, 0.19g of1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-onehydrochloride and 27 μL of acetic acid were added. Then, 59 mg of sodiumcyanoborohydride was added thereto and the mixture was stirred at roomtemperature for 4 hours. To the reaction mixture, chloroform and asaturated aqueous sodium hydrogen carbonate solution were added. Theorganic layer was separated, washed with water and a saturated aqueoussodium chloride solution and dried over anhydrous magnesium sulfate, andthe solvent was distilled off under reduced pressure. The resultantresidue was purified by basic silica gel column chromatography usinggradient elution with chloroform:methanol=19:1 to 86:14 to obtain 0.13 gof7-methoxy-1-(2-(4-(((4-methoxy-5-methylpyridin-2-yl)methyl)amino)piperidin-1-yl)ethyl)-1,5-naphthyridin-2(1H)-oneas a yellow oily substance.

¹H-NMR (CDCl₃) δ: 1.40-1.52 (2H, m), 1.88-1.97 (2H, m), 2.14 (3H, s),2.14-2.23 (2H, m), 2.50-2.60 (1H, m), 2.62-2.68 (2H, m), 2.94-3.03 (2H,m), 3.86 (2H, s), 3.88 (3H, s), 3.97 (3H, s), 4.34-4.40 (2H, m), 6.74(1H, d, J=9.8 Hz), 6.79 (1H, s), 7.25 (1H, d, J=2.4 Hz), 7.84 (1H, d,J=9.8 Hz), 8.16 (1H, s), 8.28 (1H, d, J=2.4 Hz)

EXAMPLE 129

By the same technique as in Example 8,7-methoxy-1-(2-(4-(((4-methoxy-5-methylpyridin-2-yl)methyl)amino)piperidin-1-yl)ethyl)-1,5-naphthyridin-2(1H)-onehydrochloride was obtained from7-methoxy-1-(2-(4-(((4-methoxy-5-methylpyridin-2-yl)methyl)amino)piperidin-1-yl)ethyl)-1,5-naphthyridin-2(1H)-one.

¹H-NMR (D₂O) δ: 1.79-1.92 (2H, m), 2.22 (3H, s), 2.30-2.40 (2H, m),3.02-3.17 (2H, m), 3.23-3.35 (1H, m), 3.42-3.53 (2H, m), 3.74-3.86 (2H,m), 4.03 (3H, s), 4.05 (3H, s), 4.26 (2H, s), 4.67-4.80 (2H, m), 6.87(1H, d, J=9.8 Hz), 7.23-7.25 (1H, m), 7.44 (1H, d, J=2.2 Hz), 8.05 (1H,d, J=9.8 Hz), 8.25 (1H, s), 8.40 (1H, d, J=2.2 Hz)

EXAMPLE 130

To a suspension of 0.10 g of1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-onehydrochloride in 2 mL of methanol, 0.14 g of a 28% sodiummethoxide/methanol solution, 40 mg of5-ethyl-4-methoxypyridine-2-carbaldehyde and 14 μL of acetic acid wereadded. Then, 30 mg of sodium cyanoborohydride was added thereto, and themixture was stirred at room temperature for 5 hours. To the reactionmixture, chloroform and a saturated aqueous sodium hydrogen carbonatesolution were added. The organic layer was separated, washed with waterand a saturated aqueous sodium chloride solution and dried overanhydrous magnesium sulfate, and the solvent was distilled off underreduced pressure. The resultant residue was purified by basic silica gelcolumn chromatography using gradient elution withchloroform:methanol=9:1 to 86:14 to obtain 51 mg of1-(2-(4-(((5-ethyl-4-methoxypyridin-2-yl)methyl)amino)piperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-oneas a yellow oily substance.

¹H-NMR (CDCl₃) δ: 1.18 (3H, t, 7.6 Hz), 1.41-1.55 (2H, m), 1.89-1.98(2H, m), 2.12-2.24 (2H, m), 2.51-2.68 (5H, m), 2.93-3.03 (2H, m),3.83-3.90 (5H, m), 3.97 (3H, s), 4.33-4.40 (2H, m), 6.74 (1H, d, J=9.6Hz), 6.79 (1H, s), 7.24-7.30 (1H, m), 7.84 (1H, d, J=9.6 Hz), 8.17 (1H,s), 8.28 (1H, d, J=2.4 Hz)

EXAMPLE 131

By the same technique as in Example8,1-(2-(4-(((5-ethyl-4-methoxypyridin-2-yl)methyl)amino)piperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-onehydrochloride was obtained from1-(2-(4-(((5-ethyl-4-methoxypyridin-2-yl)methyl)amino)piperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-one.

¹H-NMR (D₂O) δ: 1.20 (3H, t, J=7.6 Hz), 1.79-1.94 (2H, m), 2.32-2.40(2H, m), 2.68 (2H, q, J=7.6 Hz), 3.12-3.32 (3H, m), 3.51-3.57 (2H, m),3.80-3.89 (2H, m), 4.04 (6H, s), 4.26 (2H, s), 4.70-4.90 (2H, m), 6.86(1H, d, J=9.9 Hz), 7.28 (1H, s), 7.42-7.45 (1H, m), 8.05 (1H, d, J=9.9Hz), 8.26 (1H, s), 8.39 (1H, d, J=2.2 Hz)

EXAMPLE 132

To a suspension of 0.20 g or1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-onehydrochloride in 2 mL of methanol, 0.28 g of a 28% sodiummethoxide/methanol solution, 73 mg of5-methoxy-4-methylpyridine-2-carbaldehyde and 28 μL of acetic acid wereadded. Then, 61 mg of sodium cyanoborohydride was added thereto, and themixture was stirred at room temperature for 1 hour 30 minutes. To thereaction mixture, chloroform, a saturated aqueous sodium hydrogencarbonate solution and water were added. The organic layer wasseparated, and the aqueous layer was extracted with chloroform. Theorganic layer and the extract were combined, the resultant solution waswashed with water and a saturated aqueous sodium chloride solution anddried over anhydrous magnesium sulfate, and the solvent was distilledoff under reduced pressure. The resultant residue was purified by basicsilica gel column chromatography using gradient elution withchloroform:methanol=93:7 to 86:14 to obtain 82 mg of7-methoxy-1-(2-(4-(((5-methoxy-4-methylpyridin-2-yl)methyl)amino)piperidin-1-yl)ethyl)-1,5-naphthyridin-2(1H)-oneas a light yellow solid.

¹H-NMR (CDCl₃) δ: 1.40-1.53 (2H, m), 1.89-1.98 (2H, m), 2.13-2.23 (2H,m), 2.22 (3H, s), 2.50-2.60 (1H, m), 2.62-2.68 (2H, m), 2.93-3.03 (2H,m), 3.83 (2H, s), 3.90 (3H, s), 3.97 (3H, s), 4.34-4.39 (2H, m), 6.74(1H, d, J=9.8 Hz), 7.08 (1H, s), 7.24-7.28 (1H, m), 7.84 (1H, d, J=9.8Hz), 8.08 (1H, s), 8.27 (1H, d, J=2.2 Hz)

EXAMPLE 133

By the same technique as in Example 30,7-methoxy-1-(2-(4-(((5-(3-thienyl)isoxazol-3-yl)methyl)amino)piperidin-1-yl)ethyl)-1,5-naphthyridin-2(1H)-onewas obtained from1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-onehydrochloride and 5-(3-thienyl)isoxazole-3-carbaldehyde.

¹H-NMR (CDCl₃) δ: 1.38-1.50 (2H, m), 1.89-1.97 (2H, m), 2.15-2.25 (2H,m), 2.54-2.68 (3H, m), 2.95-3.03 (2H, m), 3.93 (2H, s), 3.98 (3H, s),4.35-4.39 (2H, m), 6.39 (1H, s), 6.74 (1H, d, J=9.6 Hz), 7.23 (1H, d,J=2.2 Hz), 7.38-7.43 (2H, m), 7.77 (1H, dd, J=2.8, 1.4 Hz), 7.84 (1H, d,J=9.6 Hz), 8.28 (1H, d, J=2.2 Hz)

EXAMPLE 134

To a suspension of 0.14 g of1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-onehydrochloride in 5 mL of methanol, 0.14 g of a 28% sodiummethoxide/methanol solution, 46 mg of6-(3-thienyl)pyridine-2-carbaldehyde, 0.10 g of molecular sieves 3 A, 28μL of acetic acid and 15 mg of sodium cyanoborohydride were added atroom temperature, and the mixture was stirred at the same temperaturefor 3 hours. To the reaction mixture, a saturated aqueous sodiumhydrogen carbonate solution and chloroform were added, the organic layerwas separated, washed with a saturated aqueous sodium chloride solutionand dried over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure. The resultant residue was purifiedby basic silica gel column chromatography using an eluent ofchloroform:methanol=30:1. To a solution of the resultant residue in 2 mLof ethyl acetate, 2 mL of a 4 mol/L hydrogen chloride/ethyl acetatesolution was added, and the mixture was stirred at room temperature for30 minutes. The solid was filtered off to obtain 97 mg of7-methoxy-1-(2-(4-(((6-(3-thienyl)pyridin-2-yl)methyl)amino)piperidin-1-yl)ethyl)-1,5-naphthyridin-2(1H)-onehydrochloride as a yellow solid.

¹H-NMR (D₂O) δ: 2.07-2.23 (2H, m), 2.54-2.66 (2H, m), 3.20-3.36 (2H, m),3.59-3.67 (2H, m), 3.73-3.83 (1H, m), 3.98-4.10 (2H, m), 4.07 (3H, s),4.54-4.61 (2H, m), 4.70-4.90 (2H, m), 6.92 (1H, d, J=9.8 Hz), 7.41-7.65(3H, m), 7.70-7.80 (1H, m), 7.87-7.92 (1H, m), 7.97-8.10 (1H, m), 8.05(1H, d, J=9.8 Hz), 8.14 (1H, s), 8.44 (1H, s)

EXAMPLE 135

To a suspension of 0.20 g of1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-onehydrochloride in 2 mL of methanol, 0.28 g of a 28% sodiummethoxide/methanol solution and 28 μL of acetic acid were added. Theretowas added 75 mg of 5-fluoro-6-methoxynicotinaldehyde, then, 61 mg ofsodium cyanoborohydride was added thereto, and the mixture was stirredat room temperature for 1 hour 20 minutes. Thereto was further added 62mg of sodium cyanoborohydride, and the mixture was stirred at roomtemperature for 1 hour 30 minutes, and then stirred at 30 to 35° C. for1 hour. To the reaction mixture, chloroform and a saturated aqueoussodium hydrogen carbonate solution were added. The organic layer wasseparated, and the aqueous layer was extracted with chloroform. Theorganic layer and the extract were combined, the resultant solution waswashed with water and a saturated aqueous sodium chloride solution anddried over anhydrous magnesium sulfate, and the solvent was distilledoff under reduced pressure. The resultant residue was purified by basicsilica gel column chromatography using gradient elution withchloroform:methanol=19:1 to 9:1, diethyl ether was added to theresultant light yellow oily substance, and the solid was filtered off toobtain 97 mg of1-(2-(4-(((5-fluoro-6-methoxypyridin-3-yl)methyl)amino)piperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-oneas a slightly yellow solid.

¹H-NMR (CDCl₃) δ: 1.35-1.46 (2H, m), 1.86-1.95 (2H, m), 2.15-2.23 (2H,m), 2.47-2.58 (1H, m), 2.62-2.68 (2H, m), 2.92-3.02 (2H, m), 3.75 (2H,m), 3.98 (3H, s), 4.01 (3H, s), 4.33-4.40 (2H, m), 6.74 (1H, d, J=9.8Hz), 7.23 (1H, d, J=2.3 Hz), 7.38 (1H, dd, J=11.0, 2.0 Hz), 7.82-7.86(2H, m), 8.28 (1H, d, J=2.3 Hz)

EXAMPLE 136

To a suspension of 0.14 g of1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-onehydrochloride in 2 mL of methanol, 0.20 g of a 28% sodiummethoxide/methanol solution, 53 mg of 6-ethyl-5-fluoronicotinaldehydeand 20 μL of acetic acid were added. Then, 43 mg of sodiumcyanoborohydride was added thereto, and the mixture was stirred at roomtemperature for 1 hour 20 minutes. Thereto was further added 43 mg ofsodium cyanoborohydride, and the mixture was stirred at room temperaturefor 1 hour, and then stirred at 30 to 40° C. for 1 hour. To the reactionmixture, chloroform and a saturated aqueous sodium hydrogen carbonatesolution were added. The organic layer was separated, and the aqueouslayer was extracted with chloroform. The organic layer and the extractwere combined, the resultant solution was washed with water and asaturated aqueous sodium chloride solution and dried over anhydrousmagnesium sulfate, and the solvent was distilled off under reducedpressure. The resultant residue was purified by basic silica gel columnchromatography using gradient elution with chloroform:methanol=93:7 to9:1 to obtain 53 mg of1-(2-(4-(((6-ethyl-5-fluoropyridin-3-yl)methyl)amino)piperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-oneas a light yellow oily substance.

¹H-NMR (CDCl₃) δ: 1.29 (3H, t, J=7.6 Hz), 1.36-1.47 (2H, m), 1.87-1.96(2H, m), 2.15-2.24 (2H, m), 2.47-2.57 (1H, m), 2.62-2.68 (2H, m), 2.86(2H, dd, J=7.6, 2.0 Hz), 2.95-3.02 (2H, m), 3.82 (2H, s), 3.98 (3H, s),4.33-4.40 (2H, m), 6.75 (1H, d, J=9.6 Hz), 7.20-7.24 (1H, m), 7.34-7.39(1H, m), 7.85 (1H, d, J=9.6 Hz), 8.25-8.27 (1H, m), 8.28 (1H, d, J=2.4Hz)

EXAMPLE 137

By the same technique as in Example8,1-(2-(4-(((6-ethyl-5-fluoropyridin-3-yl)methyl)amino)piperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-onehydrochloride was obtained from1-(2-(4-(((6-ethyl-5-fluoropyridin-3-yl)methyl)amino)piperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-one.

¹H-NMR (D₂O) δ: 1.30 (3H, t, J=7.7 Hz), 2.00-2.14 (2H, m), 2.53-2.61(2H, m), 2.99 (2H, q, J=7.7 Hz), 3.23-3.35 (2H, m), 3.61-3.77 (3H, m),3.96-4.05 (2H, m), 4.05 (3H, s), 4.47 (2H, s), 4.64-4.90 (2H, m), 6.90(1H, d, J=10.0 Hz), 7.51 (1H, s), 8.02 (1H, d, J=9.2 Hz), 8.07 (1H, d,J=10.0 Hz), 8.41-8.43 (1H, m), 8.51 (1H, s)

EXAMPLE 138

By the same technique as in Example 79,7-methoxy-1-(2-(4-(((5-methyl-4-oxo-4H-pyran-2-yl)methyl)amino)piperidin-1-yl)ethyl)-1,5-naphthyridin-2(1H)-onewas obtained from1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-onehydrochloride and 5-methyl-4-oxo-4H-pyran-2-carbaldehyde.

¹H-NMR (CDCl₃) δ: 1.30-1.50 (2H, m), 1.80-1.95 (5H, m), 2.10-2.25 (2H,m), 2.45-2.55 (1H, m), 2.60-2.70 (2H, m), 2.90-3.05 (2H, m), 3.66 (2H,s), 3.98 (3H, s), 4.30-4.45 (2H, m), 6.33 (1H, s), 6.74 (1H, d, J=9.6Hz), 7.21-7.25 (1H, m), 7.66 (1H, s), 7.85 (1H, d, J=9.6 Hz), 8.28 (1H,d, J=2.4 Hz)

EXAMPLE 139

To a suspension of 0.20 g of1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-onehydrochloride in 2 mL of methanol, 0.28 g of a 28% sodiummethoxide/methanol solution, 94 mg of5-fluoro-6-(pyrrolidin-1-yl)nicotinaldehyde and 28 μL of acetic acidwere added. Then, 61 mg of sodium cyanoborohydride was added thereto,and the mixture was stirred at room temperature for 2 hours 20 minutes.To the reaction mixture, chloroform, a saturated aqueous sodium hydrogencarbonate solution and water were added. The organic layer wasseparated, and the aqueous layer was extracted with chloroform. Theorganic layer and the extract were combined, the resultant solution waswashed with water and a saturated aqueous sodium chloride solution anddried over anhydrous magnesium sulfate, and the solvent was distilledoff under reduced pressure. The resultant residue was purified by basicsilica gel column chromatography using gradient elution withchloroform:methanol=95:5 to 9:1, thereto was added diethyl ether, andthe solid was filtered off to obtain 91 mg of1-(2-(4-(((5-fluoro-6-(pyrrolidin-1-yl)pyridin-3-yl)methyl)amino)piperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-oneas a slightly yellow solid.

¹H-NMR (CDCl₃) δ: 1.34-1.47 (2H, m), 1.85-1.99 (6H, m), 2.12-2.23 (2H,m), 2.47-2.55 (1H, m), 2.61-2.67 (2H, m), 2.92-3.01 (2H, m), 3.58-3.65(4H, m), 3.67 (2H, s), 3.98 (3H, s), 4.33-4.40 (2H, m), 6.74 (1H, d,J=9.6 Hz), 7.18 (1H, d, J=15.6 Hz), 7.22-7.25 (1H, m), 7.81 (1H, s),7.84 (1H, d, J=9.6 Hz), 8.28 (1H, d, J=2.2 Hz)

EXAMPLE 140

By the same technique as in Example 30,1-(2-(4-(((5-(2-furyl)isoxazol-3-yl)methyl)amino)piperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-onewas obtained from1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-onehydrochloride and 5-(2-furyl)isoxazole-3-carbaldehyde.

¹H-NMR (CDCl₃) δ: 1.36-1.49 (2H, m), 1.87-1.97 (2H, m), 2.15-2.25 (2H,m), 2.52-2.62 (1H, m), 2.65 (2H, t, J=7.1 Hz), 2.94-3.02 (2H, m), 3.93(2H, s), 3.97 (3H, s), 4.36 (2H, t, J=7.1 Hz), 6.44 (1H, s), 6.53 (1H,dd, J=3.4, 1.7 Hz), 6.74 (1H, d, J=9.6 Hz), 6.89 (1H, d, J=3.4 Hz),7.21-7.24 (1H, m), 7.54 (1H, d, J=1.7 Hz), 7.84 (1H, d, J=9.6 Hz), 8.28(1H, d, J=2.0 Hz)

EXAMPLE 141

By the same technique as in Example 134,7-methoxy-1-(2-(4-(((5-(2-thienyl)pyridin-3-yl)methyl)amino)piperidin-1-yl)ethyl)-1,5-naphthyridin-2(1H)-onehydrochloride was obtained from1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-onehydrochloride and 5-(2-thienyl)nicotinaldehyde.

¹H-NMR (D₂O) δ: 2.04-2.19 (2H, m), 2.57-2.67 (2H, m), 3.24-3.38 (2H, m),3.60-3.70 (2H, m), 3.75-3.86 (1H, m), 4.01-4.09 (2H, m), 4.06 (3H, s),4.58-4.64 (2H, m), 4.71-4.87 (2H, m), 6.90 (1H, d, J=9.6 Hz), 7.29 (1H,dd, J=5.0, 3.8 Hz), 7.48-7.59 (1H, m), 7.71-7.79 (2H, m), 8.07 (1H, d,J=9.6 Hz), 8.43 (1H, d, J=2.2 Hz), 8.74-8.94 (2H, m), 9.10-9.20 (1H, m)

EXAMPLE 142

By the same technique as in Example 30,7-methoxy-1-(2-(4-(((6-(2-thienyl)pyridin-3-yl)methyl)amino)piperidin-1-yl)ethyl)-1,5-naphthyridin-2(1H)-onewas obtained from1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-onehydrochloride and 6-(2-thienyl)nicotinaldehyde.

¹H-NMR (CDCl₃) δ: 1.38-1.50 (2H, m), 1.87-1.97 (2H, m), 2.14-2.25 (2H,m), 2.49-2.70 (3H, m), 2.95-3.03 (2H, m), 3.84 (2H, s), 3.98 (3H, s),4.35-4.39 (2H, m), 6.74 (1H, d, J=9.6 Hz), 7.09-7.14 (1H, m), 7.20-7.25(1H, m), 7.38 (1H, d, J=5.1 Hz), 7.57 (1H, d, J=3.6 Hz), 7.61-7.72 (2H,m), 7.84 (1H, d, J=9.6 Hz), 8.28 (1H, d, J=1.9 Hz), 8.48-8.52 (1H, m)

EXAMPLE 143

By the same technique as in Example 30,7-fluoro-1-(2-(4-(((5-(2-furyl)isoxazol-3-yl)methyl)amino)piperidin-1-yl)ethyl)-1,5-naphthyridin-2(1H)-onewas obtained from1-(2-(4-aminopiperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-onehydrochloride and 5-(2-furyl)isoxazole-3-carbaldehyde.

¹H-NMR (CDCl₃) δ: 1.35-1.47 (2H, m), 1.87-1.96 (2H, m), 2.14-2.24 (2H,m), 2.53-2.60 (1H, m), 2.65 (2H, t, J=7.0 Hz), 2.92-2.99 (2H, m), 3.93(2H, s), 4.32 (2H, t, J=7.0 Hz), 6.44 (1H, s), 6.53 (1H, dd, J=3.2, 2.0Hz), 6.86 (1H, d, J=9.6 Hz), 6.89 (1H, d, J=3.2 Hz), 7.50-7.58 (2H, m),7.88 (1H, d, J=9.6 Hz), 8.42 (1H, d, J=2.0 Hz)

EXAMPLE 144

To a suspension of 60 mg of1-(2-(4-((3,4-dihydro-2H-pyrano(2,3-c)pyridin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-onehydrochloride in 2 mL of methanol, 60 mg of a 28% sodiummethoxide/methanol solution, and the mixture was heated under refluxwhile stirring for 4 hours. Thereto were added water and ethyl acetate,the organic layer was separated, and the aqueous layer was saturatedwith sodium chloride, and then extracted with ethyl acetate twice. Theorganic layer and the extract were combined, the resultant solution wasdried over anhydrous magnesium sulfate, and the solvent was distilledoff under reduced pressure. To the resultant residue, 1 mL of ethylacetate was added, and 1 mL of a 4.0 mol/L hydrogen chloride/ethylacetate solution was added at room temperature. The solvent wasdistilled off under reduced pressure, ethyl acetate was added to theresultant residue, and the solid was filtered off to obtain 31 mg of1-(2-(4-((3,4-dihydro-2H-pyrano(2,3-c)pyridin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-onehydrochloride as a yellow solid.

¹H-NMR (D₂O) δ: 2.00-2.12 (4H, m), 2.50-2.60 (2H, m), 2.92 (2H, t, J=6.2Hz), 3.20-3.34 (2H, m), 3.60-3.74 (3H, m), 3.98-4.07 (2H, m), 4.05 (3H,s), 4.34 (2H, t, J=5.2 Hz), 4.43 (2H, s), 4.70-4.90 (2H, m), 6.89 (1H,d, J=9.9 Hz), 7.48-7.52 (2H, m), 8.07 (1H, d, J=9.9 Hz), 8.18 (1H, s),8.42 (1H, d, J=1.7 Hz)

EXAMPLE 145

By the same technique as in Example 1, tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(7-fluoro-4-methyl-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)(piperidin-4-yl)carbamatewas obtained from(7-fluoro-4-methyl-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde andtert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(piperidin-4-yl)carbamate.

¹H-NMR (CDCl₃) δ: 1.30-1.70 (13H, m), 2.07-2.25 (2H, m), 2.53 (3H, d,J=1.0 Hz), 2.59 (2H, t, J=7.1 Hz), 2.94-3.02 (2H, m), 4.04-4.18 (1H, m),4.20-4.48 (8H, m), 6.70-6.76 (2H, m), 7.41-7.48 (1H, m), 8.05 (1H, s),8.41 (1H, d, J=2.2 Hz)

EXAMPLE 146

By the same technique as in Example4,1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-7-fluoro-4-methyl-1,5-naphthyridin-2(1H)-onehydrochloride was obtained from tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(7-fluoro-4-methyl-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate.

¹H-NMR (D₂O) δ: 2.01-2.16 (2H, m), 2.53-2.62 (2H, m), 2.56 (3H, s),3.22-3.36 (2H, m), 3.60-3.67 (2H, m), 3.72-3.82 (1H, m), 3.97-4.08 (2H,m), 4.48-4.53 (2H, m), 4.57 (2H, s), 4.61-4.66 (2H, m), 4.70-4.78 (2H,m), 6.89 (1H, s), 7.53 (1H, s), 7.93 (1H, dd, J=10.4, 2.2 Hz), 8.41 (1H,s), 8.55 (1H, d, J=2.2 Hz)

EXAMPLE 147

By the same technique as in Example 30,1-(2-(4-(((5-(2-furyl)pyridin-3-yl)methyl)amino)piperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-onewas obtained from1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-onehydrochloride and 5-(2-furyl)nicotinaldehyde.

¹H-NMR (CDCl₃) δ: 1.38-1.54 (2H, m), 1.89-2.00 (2H, m), 2.14-2.28 (2H,m), 2.52-2.62 (1H, m), 2.66 (2H, t, J=7.3 Hz), 2.97-3.05 (2H, m), 3.87(2H, s), 3.98 (3H, s), 4.38 (2H, t, J=7.3 Hz), 6.52 (1H, dd, J=3.3, 1.8Hz), 6.73-6.77 (2H, m), 7.23-7.27 (1H, m), 7.53 (1H, d, J=1.4 Hz), 7.85(1H, d, J=9.8 Hz), 7.92-7.96 (1H, s), 8.28 (1H, d, J=2.2 Hz), 8.44 (1H,d, J=2.0 Hz), 8.82 (1H, d, J=2.0 Hz)

EXAMPLE 148

To a solution of 72 mg of tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(7-fluoro-4-methyl-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamatein 2.5 mL of methanol, 77 mg of a 28% sodium methoxide/methanol solutionwas added at room temperature, and the mixture was heated under refluxwhile stirring for 2 hours. After cooling to room temperature, water andchloroform were added to the reaction mixture, the organic layer wasseparated, and the aqueous layer was extracted with chloroform. Theorganic layer and the extract were combined, the resultant solution waswashed with a saturated aqueous sodium chloride solution and dried overanhydrous magnesium sulfate, and the solvent was distilled off underreduced pressure. The resultant residue was purified by basic silica gelcolumn chromatography using an eluent of chloroform to obtain 82 mg oftert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(7-methoxy-4-methyl-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamateas a light brown oily substance.

¹H-NMR (CDCl₃) δ: 1.32-1.72 (13H, m), 2.07-2.25 (2H, m), 2.51 (3H, d,J=1.0 Hz), 2.56-2.62 (2H, m), 2.96-3.05 (2H, m), 3.95 (3H, s), 4.05-4.17(1H, m), 4.25-4.45 (8H, m), 6.62 (1H, d, J=1.0 Hz), 6.71-6.76 (1H, m),7.16 (1H, d, J=2.4 Hz), 8.05 (1H, s), 8.28 (1H, d, J=2.4 Hz)

EXAMPLE 149

By the same technique as in Example4,1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-4-methyl-1,5-naphthyridin-2(1H)-onehydrochloride was obtained from tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(7-methoxy-4-methyl-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate.

¹H-NMR (D₂O) δ: 1.98-2.14 (2H, m), 2.50-2.61 (2H, m), 2.54 (3H, s),3.20-3.35 (2H, m), 3.58-3.66 (2H, m), 3.68-3.79 (1H, m), 3.95-4.09 (2H,m), 4.05 (3H, s), 4.45-4.50 (2H, m), 4.51 (2H, s), 4.56-4.62 (2H, m),4.71-4.89 (2H, m), 6.77-6.80 (1H, m), 7.43 (1H, s), 7.46 (1H, d, J=2.3Hz), 8.35 (1H, s), 8.38 (1H, d, J=2.3 Hz)

EXAMPLE 150

By the same technique as in Example 1, tert butyl(1-(2-(7-(difluoromethoxy)-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)carbamatewas obtained from(7-(difluoromethoxy)-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde andtert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(piperidin-4-yl)carbamate.

¹H-NMR (CDCl₃) δ: 1.30-1.70 (13H, m), 2.08-2.26 (2H, m), 2.58-2.65 (2H,m), 2.92-3.01 (2H, m), 4.00-4.18 (1H, m), 4.22-4.48 (8H, m), 6.70 (1H,t, J=72.1 Hz), 6.73 (1H, s), 6.86 (1H, d, J=9.9 Hz), 7.58 (1H, d, J=2.1Hz), 7.88 (1H, d, J=9.8 Hz), 8.05 (1H, s), 8.41 (1H, d, J=2.1 Hz)

EXAMPLE 151

By the same technique as in Example 4,7-(difluoromethoxy)-1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-1,5-naphthyridin-2(1H)-onehydrochloride was obtained from tert-butyl(1-(2-(7-(difluoromethoxy)-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)carbamate.

¹H-NMR (D₂O) δ: 1.99-2.14 (2H, m), 2.50-2.60 (2H, m), 3.22-3.34 (2H, m),3.59-3.78 (3H, m), 3.96-4.06 (2H, m), 4.44-4.50 (2H, m), 4.48 (2H, s),4.54-4.60 (2H, m), 4.70-4.88 (2H, m), 7.01 (1H, d, J=9.8 Hz), 7.06 (1H,t, J=72.2 Hz), 7.39 (1H, s), 7.87 (1H, d, J=2.1 Hz), 8.10 (1H, d, J=9.8Hz), 8.33 (1H, s), 8.57 (1H, d, J=2.1 Hz)

EXAMPLE 152

To a suspension of 86 mg of1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-onehydrochloride in 4 mL of methanol, 33 mg of1,5-naphthyridine-3-carbaldehyde, 0.12 g of a 28% sodiummethoxide/methanol solution and 12 μL of acetic acid were added. Then,26 mg of sodium cyanoborohydride was added thereto, and the mixture wasstirred at room temperature for 4 hours. To the reaction mixture,chloroform, a saturated aqueous sodium hydrogen carbonate solution andwater were added. The organic layer was separated and the aqueous layerwas extracted with chloroform. The organic layer and the extract werecombined, the resultant solution was washed with water and a saturatedaqueous sodium chloride solution and dried over anhydrous magnesiumsulfate, and the solvent was distilled off under reduced pressure. Theresultant residue was purified by basic silica gel column chromatographyusing gradient elution with chloroform:methanol=87:13 to 85:15 to obtain11 mg of7-methoxy-1-(2-(4-((1,5-naphthyridin-3-ylmethyl)amino)piperidin-1-yl)ethyl)-1,5-naphthyridin-2(1H)-oneas a light yellow oily substance.

¹H-NMR (CDCl₃) δ: 1.42-1.53 (2H, m), 1.93-2.00 (2H, m), 2.14-2.26 (2H,m), 2.56-2.69 (3H, m), 2.96-3.40 (2H, m), 3.98 (3H, s), 4.10 (2H, s),4.35-4.39 (2H, m), 6.74 (1H, d, J=9.8 Hz), 7.21-7.25 (1H, m), 7.62 (1H,dd, J=8.5, 4.3 Hz), 7.84 (1H, d, J=9.8 Hz), 8.28 (1H, d, J=2.4 Hz),8.31-8.34 (1H, m), 8.38-8.42 (1H, m), 8.97 (1H, dd, J=4.3, 1.6 Hz), 8.99(1H, d, J=2.0 Hz)

EXAMPLE 153

By the same technique as in Example 103,1-(2-(4-(((6-(2-furyl)pyrazin-2-yl)methyl)amino)piperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-onehydrochloride was obtained from1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-onehydrochloride and 6-(2-furyl)pyrazine-2-carbaldehyde.

¹H-NMR (CD₃OD) δ: 2.06-2.20 (2H, m), 2.46-2.59 (2H, m), 3.04-3.70 (5H,m), 3.85-4.01 (2H, m), 4.08 (3H, s), 4.59 (2H, s), 4.70-5.08 (2H, m),6.70 (1H, dd, J=3.6, 1.8 Hz), 6.80 (1H, d, J=9.6 Hz), 7.40 (1H, d, J=3.6Hz), 7.53-7.59 (1H, m), 7.79-7.82 (1H, m), 7.99 (1H, d, J=9.6 Hz), 8.34(1H, d, J=2.2 Hz), 8.58 (1H, s), 9.02 (1H, s)

EXAMPLE 154

To a solution of 0.10 g of tert-butyl(1-(2-(7-bromo-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)carbamatein 2 mL of dioxane, 90 mg of 2-tributylstannyloxazole and 17 mg ofbis(tri-tert-butylphosphine)palladium(0) were added under a nitrogenatmosphere, and the mixture was heated under reflux while stirring for 6hours 30 minutes. The resultant residue was purified by flash silica gelcolumn chromatography using gradient elution withchloroform:methanol=98:2 to 95:5 to obtain 87 mg of tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(7-(1,3-oxazol-2-yl)-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamateas a yellow oily substance.

¹H-NMR (CDCl₃) δ: 1.30-1.86 (13H, m), 2.12-2.25 (2H, m), 2.67 (2H, t,J=6.7 Hz), 2.97-3.06 (2H, m), 4.00-4.42 (9H, m), 6.71 (1H, s), 6.95 (1H,d, J=9.8 Hz), 7.34 (1H, s), 7.86 (1H, s), 7.93 (1H, d, J=9.8 Hz), 8.05(1H, s), 8.44 (1H, s), 9.18 (1H, d, J=1.5 Hz)

EXAMPLE 155

By the same technique as in Example2,1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-7-(1,3-oxazol-2-yl)-1,5-naphthyridin-2(1H)-onehydrochloride was obtained from tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(7-(1,3-oxazol-2-yl)-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate.

¹H-NMR (D₂O) δ: 2.00-2.15 (2H, m), 2.50-2.60 (2H, m), 3.24-3.36 (2H, m),3.63-3.76 (3H, m), 3.95-4.15 (2H, m), 4.42-4.58 (6H, m), 4.70-4.95 (2H,m), 7.10 (1H, d, J=9.8 Hz), 7.35 (1H, s), 7.45 (1H, s), 8.10 (1H, s),8.14 (1H, d, J=9.8 Hz), 8.31 (1H, s), 8.56 (1H, s), 9.19 (1H, d, J=1.5Hz)

EXAMPLE 156

By the same technique as in Example 154, tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(2-oxo-7-(1,3-thiazol-2-yl)-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamatewas obtained from tert-butyl(1-(2-(7-bromo-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)carbamate.

¹H-NMR (CDCl₃) δ: 1.12-1.90 (13H, m), 2.10-2.23 (2H, m), 2.62-2.75 (2H,m), 2.98-3.08 (2H, m), 4.20-4.48 (9H, m), 6.70 (1H, s), 6.94 (1H, d,J=9.8 Hz), 7.46-7.52 (1H, m), 7.92 (1H, d, J=9.8 Hz), 7.95-7.99 (1H, m),8.04 (1H, s), 8.42 (1H, s), 9.05 (1H, s)

EXAMPLE 157

By the same technique as in Example2,1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-7-(1,3-thiazol-2-yl)-1,5-naphthyridin-2(1H)-onehydrochloride was obtained from tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(2-oxo-7-(1,3-thiazol-2-yl)-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate.

¹H-NMR (D₂O) δ: 2.03-2.18 (2H, m), 2.53-2.64 (2H, m), 3.24-3.39 (2H, m),3.62-3.84 (3H, m), 3.99-4.10 (2H, m), 4.48-4.64 (6H, m), 4.70-4.90 (2H,m), 7.09 (1H, d, J=9.9 Hz), 7.54 (1H, s), 7.84 (1H, d, J=3.2 Hz), 8.05(1H, d, J=3.2 Hz), 8.12 (1H, d, J=9.9 Hz), 8.41 (1H, s), 8.48 (1H, s),9.08 (1H, d, J=1.5 Hz)

EXAMPLE 158

By the same technique as in Example 103,7-fluoro-1-(2-(4-((5,6,7,8-tetrahydroquinoxalin-2-ylmethyl)amino)piperidin-1-yl)ethyl)-1,5-naphthyridin-2(1H)-onehydrochloride was obtained from1-(2-(4-aminopiperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-onehydrochloride and 5,6,7,8-tetrahydroquinoxaline-2-carbaldehyde.

¹H-NMR (D₂O) δ: 1.89-1.97 (4H, m), 2.04-2.15 (2H, m), 2.52-2.62 (2H, m),2.94-3.01 (4H, m), 3.20-3.36 (2H, m), 3.63 (2H, t, J=6.0 Hz), 3.68-3.78(1H, m), 3.97-4.07 (2H, m), 4.49 (2H, s), 4.75-5.00 (2H, m), 7.00 (1H,d, J=9.8 Hz), 7.96 (1H, d, J=10.5 Hz), 8.10 (1H, d, J=9.8 Hz), 8.40 (1H,s), 8.57 (1H, s)

EXAMPLE 159

By the same technique as in Example 134,7-fluoro-1-(2-(4-(((5-(2-furyl)-1,3-oxazol-2-yl)methyl)amino)piperidin-1-yl)ethyl)-1,5-naphthyridin-2(1H)-onehydrochloride was obtained from1-(2-(4-aminopiperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-onehydrochloride and 5-(2-furyl)-1,3-oxazole-2-carbaldehyde.

¹H-NMR (D₂O) δ: 2.00-2.14 (2H, m), 2.50-2.60 (2H, m), 3.20-3.34 (2H, m),3.63 (2H, t, J=6.1 Hz), 3.68-3.80 (1H, m), 3.98-4.06 (2H, m), 4.62 (2H,s), 4.70-4.88 (2H, m), 6.60-6.70 (1H, m), 6.85 (1H, d, J=3.4 Hz), 6.99(1H, d, J=9.8 Hz), 7.40 (1H, s), 7.65 (1H, s), 7.95 (1H, d, J=9.8 Hz),8.10 (1H, d, J=9.8 Hz), 8.56 (1H, s)

EXAMPLE 160

By the same technique as in Example 117,1-(2-(3-(((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)methyl)piperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-onewas obtained from1-(2-(3-(((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)methyl)piperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-onehydrochloride.

¹H-NMR (CDCl₃) δ: 0.90-1.04 (1H, m), 1.48-2.18 (6H, m), 2.47-2.54 (2H,m), 2.60-2.68 (2H, m), 2.89-2.98 (1H.m), 3.01-3.09 (1H, m), 3.74 (2H,s), 3.97 (3H, s), 4.24-4.43 (6H, m), 6.74 (1H, d, J=9.8 Hz), 6.81 (1H,s), 7.27-7.28 (1H, m), 7.84 (1H, d, J=9.8 Hz), 8.10 (1H, s), 8.27 (1H,d, J=2.4 Hz)

EXAMPLE 161

By the same technique as in Example8,1-(2-(3-(((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)methyl)piperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-onehydrochloride was obtained from1-(2-(3-(((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)methyl)piperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-one.

¹H-NMR (D₂O) δ: 1.33-1.50 (1H, m), 1.76-1.94 (1H, m), 1.99-2.17 (2H, m),2.32-2.47 (1H, m), 2.88-3.13 (2H, m), 3.16-3.31 (2H, m), 3.54-3.68 (2H,m), 3.75-3.85 (1H, m), 3.95-4.04 (1H, m), 4.06 (3H, s), 4.44-4.65 (6H,m), 4.70-4.90 (2H, m), 6.91 (1H, d, J=9.8 Hz), 7.51 (1H, s), 7.55 (1H,d, J=2.3 Hz), 8.07 (1H, d, J=9.8 Hz), 8.38 (1H, s), 8.43 (1H, d, J=2.3Hz)

EXAMPLE 162

By the same technique as in Example 103,1-(2-(4-((3,4-dihydro-2H-pyrano(3,2-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-onehydrochloride was obtained from1-(2-(4-aminopiperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-onehydrochloride and 3,4-dihydro-2H-pyrano(3,2-c)pyridine-7-carbaldehyde.

¹H-NMR (D₂O) δ: 2.00-2.15 (4H, m), 2.50-2.64 (2H, m), 2.92 (2H, t, J=6.4Hz), 3.24-3.36 (2H, m), 3.64 (2H, t, J=5.9 Hz), 3.68-3.80 (1H, m),3.96-4.07 (2H, m), 4.51-4.59 (4H, m), 4.70-4.90 (2H, m), 7.00 (1H, d,J=9.8 Hz), 7.38 (1H, s), 7.96 (1H, dd, J=10.4, 2.2 Hz), 8.11 (1H, d,J=9.8 Hz), 8.44 (1H, s), 8.57 (1H, d, J=2.2 Hz)

EXAMPLE 163

By the same technique as in Example 144,1-(2-(4-((3,4-dihydro-2H-pyrano(3,2-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-onehydrochloride was obtained from1-(2-(4-((3,4-dihydro-2H-pyrano(3,2-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one.

¹H-NMR (D₂O) δ: 2.00-2.15 (4H, m), 2.50-2.61 (2H, m), 2.92 (2H, t, J=6.2Hz), 3.21-3.36 (2H, m), 3.64 (2H, t, J=5.9 Hz), 3.68-3.79 (1H, m),3.98-4.08 (2H, m), 4.05 (3H, s), 4.51-4.58 (2H, m), 4.56 (2H, s),4.77-4.90 (2H, m), 6.88 (1H, d, J=9.6 Hz), 7.37 (1H, s), 7.48 (1H, s),8.06 (1H, d, J=9.6 Hz), 8.41 (1H, s), 8.44 (1H, s)

EXAMPLE 164

By the same technique as in Example 1, tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(2-oxo-7-(trifluoromethyl)-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamatewas obtained from(2-oxo-7-(trifluoromethyl)-1,5-naphthyridin-1(2H)-yl)acetaldehyde andtert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(piperidin-4-yl)carbamate.

¹H-NMR (CDCl₃) δ: 1.33-1.71 (13H, m), 2.10-2.26 (2H, m), 2.63 (2H, t,J=6.6 Hz), 2.93-3.01 (2H, m), 4.07-4.18 (1H, m), 4.25-4.37 (8H, m), 6.71(1H, s), 7.02 (1H, d, J=9.8 Hz), 7.95 (1H, d, J=9.8 Hz), 8.02 (1H, s),8.05 (1H, s), 8.75 (1H, s)

EXAMPLE 165

To a solution of 80 mg of tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(2-oxo-7-(trifluoromethyl)-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamatein 1.4 mL of isopropyl alcohol, 57 μL of concentrated hydrochloric acidwas added, and the mixture was heated under reflux while stirring for 1hour 30 minutes. The reaction mixture was cooled to room temperature,and the solid was filtered off to obtain 70 mg of1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-onehydrochloride as a light brown solid.

¹H-NMR (D₂O) δ: 1.94-2.07 (2H, m), 2.44-2.52 (2H, m), 3.10-3.20 (2H, m),3.50-3.63 (3H, m), 3.87-3.94 (2H, m), 4.29 (2H, s), 4.36-4.46 (4H, m),4.75-4.85 (2H, m), 7.09 (1H, s), 7.17 (1H, d, J=10.0 Hz), 8.14-8.19 (2H,m), 8.39 (1H, s), 8.93 (1H, s)

EXAMPLE 166

By the same technique as in Example 3, tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(7-fluoro-6-methyl-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamatewas obtained from(7-fluoro-6-methyl-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde andtert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(piperidin-4-yl)carbamate.

¹H-NMR (CDCl₃) δ: 1.25-1.70 (13H, m), 2.05-2.25 (2H, m), 2.50-2.61 (2H,m), 2.58 (3H, d, J=2.9 Hz), 2.95-3.00 (2H, m), 4.01-4.20 (1H, m),4.23-4.40 (8H, m), 6.72 (1H, s), 6.81 (1H, d, J=9.8 Hz), 7.41 (1H, d,J=10.7 Hz), 7.81 (1H, d, J=9.8 Hz), 8.05 (1H, s)

EXAMPLE 167

To a solution of 0.48 g of tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(7-fluoro-6-methyl-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamatein 4.7 mL of isopropyl alcohol, 0.44 mL of concentrated hydrochloricacid was added, the temperature was increased to 60° C. and the mixturewas stirred for 3 hours. The reaction mixture was cooled to roomtemperature, and the solid was filtered off to obtain 0.33 g of1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-7-fluoro-6-methyl-1,5-naphthyridin-2(1H)-onehydrochloride as a white solid.

¹H-NMR (D₂O) δ: 1.99-2.14 (2H, m), 2.49-2.61 (2H, m), 2.59 (3H, d, J=2.4Hz), 3.19-3.34 (2H, m), 3.56-3.74 (3H, m), 3.94-4.04 (2H, m), 4.39 (2H,s), 4.39-4.54 (4H, m), 4.73 (2H, t, J=6.0 Hz), 6.96 (1H, d, J=9.9 Hz),7.23 (1H, s), 7.88 (1H, d, J=10.5 Hz), 8.02 (1H, d, J=9.9 Hz), 8.23 (1H,s)

EXAMPLE 168

To 0.16 g of1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-7-fluoro-6-methyl-1,5-naphthyridin-2(1H)-onehydrochloride, chloroform and a saturated aqueous sodium hydrogencarbonate solution were added, the organic layer was separated and theaqueous layer was extracted with chloroform. The organic layer and theextract were combined, the resultant solution was dried over anhydrousmagnesium sulfate, and the solvent was distilled off under reducedpressure. To the residue, 2.6 mL of methanol and 0.15 mL of a 28% sodiummethoxide/methanol solution were added, and the mixture was heated underreflux while stirring for 2 hours. The reaction mixture was cooled toroom temperature, thereto were added chloroform and a saturated aqueoussodium hydrogen carbonate solution, the organic layer was separated, andthe aqueous layer was extracted with chloroform. The organic layer andthe extract were combined, the resultant solution was dried overanhydrous magnesium sulfate, and the solvent was distilled off underreduced pressure. To the resultant residue, 1.4 mL of isopropyl alcoholand 93 μL of concentrated hydrochloric acid were added, and the mixturewas stirred at room temperature for 30 minutes. The reaction mixture wascooled with ice, and the solid was filtered off to obtain 0.15 g of1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-6-methyl-1,5-naphthyridin-2(1H)-onehydrochloride as a white solid.

¹H-NMR (D₂O) δ: 1.95-2.15 (2H, m), 2.50-2.60 (2H, m), 2.59 (3H, s),3.30-3.35 (2H, m), 3.60-3.75 (3H, m), 3.95-4.10 (2H, m), 4.09 (3H, s),4.38-4.55 (6H, m), 4.75-4.85 (2H, m), 6.91 (1H, d, J=9.8 Hz), 7.27 (1H,s), 7.49 (1H, s), 8.04 (1H, d, J=9.8 Hz), 8.26 (1H, s)

EXAMPLE 169

By the same technique as in Example 78, tert-butyl(5-(((1-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)amino)methyl)pyrazin-2-yl)carbamatewas obtained from1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-onehydrochloride and tert-butyl (5-formylpyrazin-2-yl)carbamate.

¹H-NMR (CDCl₃) δ: 1.40-1.60 (11H, m), 1.87-1.97 (2H, m), 2.13-2.25 (2H,m), 2.49-2.58 (1H, m), 2.61-2.70 (2H, m), 2.95-3.05 (2H, m), 3.91 (2H,s), 3.98 (3H, s), 4.33-4.42 (2H, m), 6.74 (1H, d, J=9.6 Hz), 7.15-7.19(1H, m), 7.84 (1H, d, J=9.6 Hz), 8.20 (1H, s), 8.28 (1H, d, J=2.4 Hz),9.19 (1H, s)

EXAMPLE 170

By the same technique as in Example 167,1-(2-(4-(((5-aminopyrazin-2-yl)methyl)amino)piperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-onehydrochloride was obtained from tert-butyl(5-(((1-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)amino)methyl)pyrazin-2-yl)carbamate.

¹H-NMR (D₂O) δ: 1.97-2.13 (2H, m), 2.49-2.60 (2H, m), 3.19-3.34 (2H, m),3.57-3.74 (3H, m), 3.96-4.07 (2H, m), 4.04 (3H, s), 4.30-4.38 (2H, m),4.78-4.80 (2H, m), 6.85-6.91 (1H, m), 7.43-7.52 (1H, m), 7.98-8.32 (2H,m), 8.06 (1H, d, J=9.8 Hz), 8.40 (1H, d, J=2.2 Hz)

EXAMPLE 171

To a solution 211 mg of1-(2-(4-aminopiperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-oneand 120 mg of 2,3-dihydro(1,4)dioxino(2,3-b)pyridine-7-carbaldehyde in22 mL of chloroform, 88 mg of acetic acid was added, and the mixture wasstirred at room temperature for 14 hours. To the reaction mixture, 232mg of sodium triacetoxyborohydride was added, and the mixture wasstirred for 2 hours. Thereto was added a saturated aqueous sodiumhydrogen carbonate solution, and the organic layer was separated. Theorganic layer was washed with a saturated aqueous sodium chloridesolution, and dried over anhydrous magnesium sulfate, and the solventwas distilled off under reduced pressure. The resultant residue waspurified by silica gel column chromatography using silica gel; SilicaGel 60N made by KANTO CHEMICAL CO., INC., and an eluent ofchloroform:methanol=10:1 to obtain 185 mg of1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-b)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-oneas a light yellow solid.

To a solution of 185 mg of1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-b)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-onein 4 mL of ethyl acetate, 2 mL of 4 mol/L hydrogen chloride/ethylacetate was added, and the mixture was stirred at room temperature for 1hour. The solid was filtered off to obtain 244 mg of1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-b)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-onehydrochloride as a white solid.

¹H-NMR (DMSO-d₆) δ: 2.01-2.12 (2H, m), 2.34-2.41 (2H, m), 3.17 (2H, s),3.24-3.35 (3H, m), 3.75-3.82 (2H, m), 4.11-4.17 (2H, m), 4.25-4.30 (2H,m), 4.41-4.45 (2H, m), 4.59-4.65 (2H, m), 6.89 (1H, d, J=9.6 Hz),7.61-7.67 (1H, m), 7.90-7.95 (1H, m), 8.01 (1H, d, J=9.6 Hz), 8.32-8.39(1H, m), 8.60-8.65 (1H, m), 9.61-9.76 (3H, m), 10.79-11.02 (1H, m)

EXAMPLE 172

To 7.00 g of (7-bromo-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde, asolution of 10.07 g of tert-butyl(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(piperidin-4-yl)carbamatein 140 mL of chloroform and 1.57 g of acetic acid were added, and themixture was stirred at room temperature for 19 hours, then, 8.77 g ofsodium triacetoxyborohydride was added thereto and the mixture wasstirred for 2 hours. To the reaction mixture, 140 mL of a saturatedaqueous sodium hydrogen carbonate solution was added, the organic layerwas separated, then washed with a saturated aqueous sodium chloridesolution and dried over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure. The resultant residue was purifiedby silica gel column chromatography using silica gel; Chromatorex-NHmade by Fuji Silysia Chemical Ltd., and gradient elution withhexane:ethyl acetate=50:50 to 5:95, and then recrystallized in 24 mL ofethanol to obtain 11.26 g of tert-butyl(1-(2-(7-bromo-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)carbamateas a white solid.

¹H-NMR (CDCl₃) δ: 1.32-1.55 (9H, m), 1.69 (4H, m), 2.20 (2H, m), 2.62(2H, t, J=6.6 Hz), 2.97 (2H, d, J=11.5 Hz), 4.12 (1H, s), 4.27 (4H, m),4.32 (4H, m), 6.72 (1H, s), 6.90 (1H, d, J=9.6 Hz), 7.85 (1H, d, J=9.6Hz), 8.01 (1H, s), 8.06 (1H, s), 8.54 (1H, d, J=1.4 Hz)

EXAMPLE 173

To 0.51 g of tert-butyl(1-(2-(7-bromo-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)carbamate,

-   18 mL of a 2 mol/L hydrogen chloride/ethanol solution was added at    room temperature, the mixture was stirred at room temperature for 59    hours, and at 50° C. for 9 hours, and then, the generated solid was    filtered off. Subsequently, the solid was suspended in 3 mL of    chloroform, thereto was added 5 mL of trifluoroacetic acid, the    mixture was stirred at room temperature for 100 minutes, and then    the solvent was distilled off under reduced pressure. The residue    was charged with 10 mL of chloroform and 3 mL of water and adjusted    to pH 10 with a 2 mol/L aqueous sodium hydroxide solution, and then    the organic layer was separated. The aqueous layer was extracted    with chloroform twice, and combined with the organic layer, the    resultant solution was washed with a saturated aqueous sodium    chloride solution and dried over anhydrous magnesium sulfate, and    the solvent was distilled off under reduced pressure. The residue    was dissolved in 2 mL of ethyl acetate and 3 mL of ethanol, and 10    mL of a 2 mol/L hydrochloric acid/ethanol solution was added    thereto, the mixture was stirred for 15 minutes, and the solvent was    distilled off under reduced pressure. To the residue, 4 mL of ethyl    acetate was added and suspended, and the solid was filtered off to    obtain 0.41 g of    7-bromo-1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-1,5-naphthyridin-2(1H)-one    hydrochloride as a slightly yellow solid.

¹H-NMR (D₂O) δ: 2.03-2.15 (2H, m), 2.59 (2H, d, J=13.3 Hz), 3.30 (2H,s), 3.64 (2H, t, J=5.7 Hz), 3.79 (1H, tt, J=11.9, 4.1 Hz), 4.04 (2H, s),4.51 (2H, dd), 4.59 (2H, s), 4.65 (2H, m), 4.75 (2H, t, J=6.2 Hz), 7.04(1H, d, J=9.6 Hz), 7.56 (1H, s), 8.05 (1H, d, J=9.6 Hz), 8.37 (1H, d,J=0.9 Hz), 8.42 (1H, s), 8.70 (1H, d, J=1.8 Hz)

EXAMPLE 174

To a solution of 0.85 g of tert-butyl(1-(2-(7-bromo-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)carbamatein 5 mL of 1,4-dioxane, 0.20 g of tert-butyl carbamate, 0.69 g of cesiumcarbonate and 13 mg of tris(benzylideneacetone)dipalladium and 24 mg of4,5-bis(diphenylphosphino)-9,9-dimethylxanthene were added, and themixture was stirred at 90° C. for 38 hours under a nitrogen atmosphere.After cooling to room temperature, the insoluble substance was separatedby filtration, and the filtrated solution was concentrated under reducedpressure. The residue was purified by silica gel column chromatographyusing silica gel; Silica Gel 60 made by KANTO CHEMICAL CO., INC., and aneluent of hexane:ethyl acetate=33:67 to 5:95 to obtain 0.68 g oftert-butyl(1-(2-(7-((tert-butoxycarbonyl)amino)-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)carbamateas a white solid.

¹H-NMR (CDCl₃) δ: 1.33-1.51 (9H, m), 1.53 (9H, s), 1.55-1.65 (2H, m),1.78 (2H, s), 2.11-2.26 (2H, m), 2.66 (2H, t, J=7.1 Hz), 3.01 (2H, d,J=10.5 Hz), 4.06-4.15 (1H, m), 4.24-4.29 (2H, m), 4.29-4.37 (5H, m),4.37-4.44 (1H, m), 6.72 (1H, s), 6.76 (1H, d, J=9.6 Hz), 7.09-7.24 (1H,m), 7.80 (1H, d, J=9.6 Hz), 8.04 (1H, s), 8.25 (1H, d, J=1.4 Hz), 8.32(1H, s)

EXAMPLE 175

To a solution of 0.66 g of tert-butyl(1-(2-(7-((tert-butoxycarbonyl)amino)-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)carbamatein 8 mL of methanol, 8 mL of a 4 mol/L hydrogen chloride/ethyl acetatesolution was added at room temperature, the mixture was stirred for 18hours, and then the solid was filtered off. Subsequently, the solid wassuspended in 3 mL of chloroform, thereto was added 6 mL oftrifluoroacetic acid at room temperature, the mixture was stirred for 2hours, and the solvent was then distilled off under reduced pressure.The residue was charged with chloroform and water and adjusted to pH 9with a 2 mol/L aqueous sodium hydroxide solution, and the organic layerwas separated. The aqueous layer was extracted with chloroform threetimes and combined with the organic layer, the resultant solution waswashed with a saturated aqueous sodium chloride solution and dried overanhydrous magnesium sulfate, and the solvent was distilled off underreduced pressure to obtain 0.31 g of7-amino-1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-1,5-naphthyridin-2(1H)-oneas a white foam.

¹H-NMR (CDCl₃) δ: 1.44-1.52 (2H, m), 1.94 (2H, d, J=12.4 Hz), 2.20 (2H,t, J=11.0 Hz), 2.51-2.57 (1H, m), 2.60-2.65 (2H, m), 2.98-3.03 (2H, m),3.80 (2H, s), 4.20 (2H, s), 4.26-4.30 (2H, m), 4.30-4.35 (4H, m), 6.63(1H, d, J=9.6 Hz), 6.82 (1H, s), 7.00 (1H, d, J=1.8 Hz), 7.76 (1H, d,J=9.6 Hz), 8.03 (1H, d, J=1.8 Hz), 8.11 (1H, s)

EXAMPLE 176

To a solution of 0.095 g of7-amino-1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-1,5-naphthyridin-2(1H)-onein 3 mL of ethanol and 2 mL of ethyl acetate, 4 mL of a 2 mol/L hydrogenchloride/ethanol solution was added at room temperature, and the mixturewas stirred at room temperature for 20 minutes, and the solvent wasdistilled off under reduced pressure. To the residue, 8 mL of diethylether was added, the residue was suspended therein, and the solid wasfiltered off to obtain 0.41 g of7-amino-1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-1,5-naphthyridin-2(1H)-onehydrochloride as a yellow solid.

¹H-NMR (CDCl₃) δ: 2.02-2.12 (2H, m), 2.56 (2H, d, J=13.3 Hz), 3.28 (2H,t, J=10.5 Hz), 3.62 (2H, t, J=6.0 Hz), 3.69-3.76 (1H, m), 3.98-4.05 (2H,m), 4.44-4.49 (4H, m), 4.54-4.58 (2H, m), 4.71 (2H, t, J=6.0 Hz), 6.83(1H, d, J=9.6 Hz), 7.37 (1H, s), 7.48 (1H, d, J=2.3 Hz), 7.99 (1H, d,J=9.6 Hz), 8.18 (1H, d, J=2.3 Hz), 8.31 (1H, s)

INDUSTRIAL APPLICABILITY

The present heterocyclic compound or salt thereof has strongantimicrobial activity and high safety and is therefore useful as anexcellent antimicrobial agent.

1. A compound represented by a general formula:

[wherein R¹ denotes an optionally substituted C₂-C₁₂ alkyl, aryl orheterocyclic group; X¹ denotes an optionally substituted C₂-C₄ alkylenegroup; X² denotes a group represented by a general formula NR² (where R²denotes a hydrogen atom, an optionally substituted lower alkyl group oran imino-protecting group) or a bond; X³ denotes a group represented bya general formula NR³ or CR⁴R⁵NR³ (where R³ denotes a hydrogen atom, anoptionally substituted lower alkyl group or an imino-protecting group;and R⁴ and R⁵ are the same or different and are each a hydrogen atom oran optionally substituted lower alkyl group, or R⁴ and R⁵ together forman oxo group) or a bond; X⁴ denotes an optionally substituted loweralkylene, lower alkenylene or lower alkynylene group or a bond; X⁵denotes an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonylgroup, a group represented by a general formula NR⁶ (where R⁶ denotes ahydrogen atom, an optionally substituted lower alkyl, lower alkenyl orlower alkynyl group or an imino-protecting group) or a bond; Y¹ denotesan optionally substituted bivalent alicyclic hydrocarbon residue or anoptionally substituted bivalent alicyclic amine residue; Z¹, Z², Z³, Z⁴,Z⁵ and Z⁶ are the same or different and are each a nitrogen atom or agroup represented by a general formula CR⁷ (where R⁷ denotes a hydrogenatom, a halogen atom, a hydroxyl group, a cyano group, a nitro group, aformyl group, an optionally protected or substituted amino group, anoptionally substituted lower alkyl, cycloalkyl, aryl, lower alkoxy,cycloalkyloxy, aralkyloxy, alkanoyl, ureido or monocyclic heterocyclicgroup, or a group represented by a general formula Q¹CONR⁸R⁹, Q¹CO₂R¹⁰or Q¹CN (where Rx and R⁹ are the same or different and are each ahydrogen atom, an optionally substituted lower alkyl, cycloalkyl,aralkyl, aryl, lower alkoxy, alkanesulfonyl or monocyclic heterocyclicgroup, or form, together with the nitrogen atom to which R⁸ and R⁹ bind,an optionally substituted cyclic amino group; R¹⁰ denotes a hydrogenatom or a carboxyl-protecting group; and Q¹ denotes an optionallysubstituted lower alkylene or lower alkenylene group or a bond)),provided that at least one of Z³, Z⁴, Z⁵ and Z⁶ is a nitrogen atom] or asalt thereof.
 2. The compound or a salt thereof according to claim 1,wherein Z¹ is a group represented by the general formula CR⁷ (where R⁷denotes a hydrogen atom, a halogen atom, a hydroxyl group, a cyanogroup, a nitro group, a formyl group, an optionally protected orsubstituted amino group, an optionally substituted lower alkyl,cycloalkyl, aryl, lower alkoxy, cycloalkyloxy, aralkyloxy, alkanoyl,ureido or monocyclic heterocyclic group, or a group represented by ageneral formula Q¹CONR⁸R⁹, Q¹CO₂R¹⁰ or Q¹CN (where R⁸ and R⁹ are thesame or different and are each a hydrogen atom, an optionallysubstituted lower alkyl, cycloalkyl, aralkyl, aryl, lower alkoxy,alkanesulfonyl or monocyclic heterocyclic group, or form, together withthe nitrogen atom to which R⁸ and R⁹ bind, an optionally substitutedcyclic amino group; R¹⁰ denotes a hydrogen atom or a carboxyl-protectinggroup; and Q¹ denotes an optionally substituted lower alkylene or loweralkenylene group or a bond)).
 3. The compound or a salt thereofaccording to claim 1, wherein Z¹ is a group represented by a generalformula CR^(7a) (where R^(7a) denotes a hydrogen atom, a halogen atom, ahydroxyl group or an optionally substituted lower alkyl or lower alkoxygroup).
 4. The compound or a salt thereof according to claim 1, whereinX¹ is an optionally substituted ethylene group.
 5. The compound or asalt thereof according to claim 1, wherein X² is NH or a bond; X³ is NH,CH₂NH or a bond; X⁴ is an optionally substituted lower alkylene group ora bond; and X⁵ is an oxygen atom, a sulfur atom, NH or a bond.
 6. Thecompound or a salt thereof according to claim 1, wherein R¹ is anoptionally substituted aryl or heterocyclic group.
 7. The compound or asalt thereof according to claim 1, wherein Y¹ is an optionallysubstituted bivalent 4-, 5- or 6-membered alicyclic hydrocarbon residueor an optionally substituted bivalent 5- or 6-membered alicyclic amineresidue.
 8. The compound or a salt thereof according to claim 1, whereinY¹ is an optionally substituted cyclohexylene, piperazinediyl orpiperidinediyl group.
 9. The compound or a salt thereof according toclaim 1, wherein Z⁵ is a group represented by a general formula CR^(7b)(where R^(7b) is a hydrogen atom, a halogen atom or an optionallysubstituted lower alkyl or lower alkoxy group).
 10. The compound or asalt thereof according to claim 1, wherein Z¹, Z² and Z⁴ are each CH; Z³is a nitrogen atom; Z⁵ is a group represented by a general formulaCR^(7d) (where R^(7d) is a halogen atom or an optionally substitutedlower alkyl or lower alkoxy group); and Z⁶ is a nitrogen atom or CH. 11.The compound or a salt thereof according to claim 1, wherein Z⁵ is agroup represented by a general formula CRA^(7e) (where R^(7e) is ahalogen atom, a lower alkyl group or a lower alkoxy group).
 12. Thecompound or a salt thereof according to claim 1, wherein X¹ is anethylene group; X² and X⁵ are each a bond; X³ is NH; and X⁴ is amethylene group.
 13. The compound or a salt thereof according to claim1, wherein Y¹ is a piperidine-1,4-diyl group (the nitrogen atom in the1-position binds to X²).
 14. The compound or a salt thereof according toclaim 1, wherein R¹ is a 2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylgroup.
 15. The compound or a salt thereof according to claim 1, whereinthe compound is selected from the group consisting of:7-chloro-1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-1,5-naphthyridin-2(1H)-one,1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one,1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-one,and5-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-3-methoxypyrido(2,3-b)pyrazin-6(5H)-one.16.7-Chloro-1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-1,5-naphthyridin-2(1H)-oneor a salt thereof. 17.1-(2-(4-((2,3-Dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-oneor a salt thereof. 18.1-(2-(4-((2,3-Dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-oneor a salt thereof. 19.5-(2-(4-((2,3-Dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-3-methoxypyrido(2,3-b)pyrazin-6(5H)-oneor a salt thereof.
 20. A compound represented by a general formula:

[wherein X^(1a) denotes an optionally substituted C₁-C₃ alkylene group;Y² denotes an optionally protected carbonyl group; Z¹, Z², Z³, Z⁴, Z⁵and Z⁶ are the same or different and are each a nitrogen atom or a grouprepresented by a general formula CR⁷ (where R⁷ denotes a hydrogen atom,a halogen atom, a hydroxyl group, a cyano group, a nitro group, a formylgroup, an optionally protected or substituted amino group, an optionallysubstituted lower alkyl, cycloalkyl, aryl, lower alkoxy, cycloalkyloxy,aralkyloxy, alkanoyl, ureido or monocyclic heterocyclic group, or agroup represented by a general formula Q¹CONR⁸R⁹, QCO₂R¹⁰ or Q¹CN (whereR⁸ and R⁹ are the same or different and are each a hydrogen atom, anoptionally substituted lower alkyl, cycloalkyl, aralkyl, aryl, loweralkoxy, alkanesulfonyl or monocyclic heterocyclic group, or form,together with the nitrogen atom to which R⁸ and R⁹ bind, an optionallysubstituted cyclic amino group; R¹⁰ denotes a hydrogen atom or acarboxyl-protecting group; and Q¹ denotes an optionally substitutedlower alkylene or lower alkenylene group or a bond)); provided that atleast one of Z³, Z⁴, Z⁵ and Z⁶ is a nitrogen atom].
 21. The compoundaccording to claim 20, wherein Z¹ is a group represented by a generalformula CR⁷ (where R⁷ denotes a hydrogen atom, a halogen atom, ahydroxyl group, a cyano group, a nitro group, a formyl group, anoptionally protected or substituted amino group, an optionallysubstituted lower alkyl, cycloalkyl, aryl, lower alkoxy, cycloalkyloxy,aralkyloxy, alkanoyl, ureido or monocyclic heterocyclic group, or agroup represented by a general formula Q¹CONR⁸R⁹, Q¹CO₂R¹⁰ or Q¹CN(where R⁸ and R⁹ are the same or different and are each a hydrogen atom,an optionally substituted lower alkyl, cycloalkyl, aralkyl, aryl, loweralkoxy, alkanesulfonyl or monocyclic heterocyclic group, or form,together with the nitrogen atom to which R⁸ and R⁹ bind, an optionallysubstituted cyclic amino group; R¹⁰ denotes a hydrogen atom or acarboxyl-protecting group; and Q¹ denotes an optionally substitutedlower alkylene or lower alkenylene group or a bond)).
 22. The compoundaccording to claim 20, wherein Z¹ is a group represented by a generalformula CR^(7a) (where R^(7a) denotes a hydrogen atom, a halogen atom, ahydroxyl group or an optionally substituted lower alkyl or lower alkoxygroup).
 23. The compound according to claim 20, wherein X^(1a) is amethylene group; and Y² is a carbonyl group.
 24. The compound accordingto claim 20, wherein Z¹, Z² and Z⁴ are each CH; Z³ is a nitrogen atom;Z⁵ is a group represented by the general formula CR^(7d) (where R^(7d)is a halogen atom or an optionally substituted lower alkyl or loweralkoxy group); and Z⁶ is a nitrogen atom or CH.
 25. The compoundaccording to claim 20, wherein Z⁵ is a group represented by the generalformula CR^(7e) (where R^(7e) is a halogen atom, a lower alkyl group ora lower alkoxy group).
 26. A compound represented by a general formula:

[wherein R^(7c) denotes a halogen atom, a hydroxyl group, a cyano group,a nitro group, a formyl group, an optionally protected or substitutedamino group, an optionally substituted lower alkyl, cycloalkyl, aryl,lower alkoxy, cycloalkyloxy, aralkyloxy, alkanoyl, ureido or monocyclicheterocyclic group, or a group represented by a general formulaQ¹CONR¹R⁹, Q¹CO₂R¹⁰ or Q¹CN (where R⁸ and R⁹ are the same or differentand are each a hydrogen atom, an optionally substituted lower alkyl,cycloalkyl, aralkyl, aryl, lower alkoxy, alkanesulfonyl or monocyclicheterocyclic group, or form, together with the nitrogen atom to which R⁸and R⁹ bind, an optionally substituted cyclic amino group; R¹⁰ denotes ahydrogen atom or a carboxyl-protecting group; Q¹ denotes an optionallysubstituted lower alkylene or lower alkenylene group or a bond); Z^(2a)and Z^(6a) are the same or different and are each a nitrogen atom or agroup represented by the general formula CR⁷ (where R⁷ denotes ahydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a nitrogroup, a formyl group, an optionally protected or substituted aminogroup, an optionally substituted lower alkyl, cycloalkyl, aryl, loweralkoxy, cycloalkyloxy, aralkyloxy, alkanoyl, ureido or monocyclicheterocyclic group, or a group represented by a general formulaQ¹CONR⁸R⁹, Q¹CO₂R¹⁰ or Q¹CN (where R⁸ and R⁹ are the same or differentand are each a hydrogen atom, an optionally substituted lower alkyl,cycloalkyl, aralkyl, aryl, lower alkoxy, alkanesulfonyl or monocyclicheterocyclic group, or form, together with the nitrogen atom to which R⁸and R⁹ bind, an optionally substituted cyclic amino group; R¹⁰ denotes ahydrogen atom or a carboxyl-protecting group; and Q¹ denotes anoptionally substituted lower alkylene or lower alkenylene group or abond))].
 27. The compound according to claim 26, wherein R^(7c) is ahalogen atom or an optionally substituted lower alkyl or lower alkoxygroup; Z²a is CH; and Z^(6a) is a nitrogen atom or CH.
 28. Anantimicrobial agent comprising the compound or a salt thereof accordingto claim 1.